Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.
Interleukin-1 (IL-1) receptor-associated kinases (IRAKs) are central components of Toll/IL-1 receptor (TIR) signaling pathways. In an attempt to discover novel signal transducers in TIR signaling, we identified human Pellino2 as an interaction partner of IRAK4. Pellino2 interacts with kinase-active as well as kinase-inactive IRAK1 and IRAK4. Furthermore, Pellino2 is one of the first substrates identified for IRAK1 and IRAK4. Functional studies using overexpression or RNAi knock-down of Pellino2 suggest a role of Pellino2 as a scaffolding protein similar to Pellino1. However, unlike Pellino1, Pellino2 does not seem to activate a specific transcription factor, but links TIR signaling to basic cellular processes.
Being one of the key kinases downstream of Toll-like receptors, IRAK1 has initially thought to be responsible for NFkappaB activation. Yet IRAK1 knock-out mice still exhibit NFkappaB activation upon lipopolysaccharide (LPS) challenge, suggesting that IRAK1 may play other un-characterized function. In this report, we show that IRAK1 is mainly involved in Stat3 activation and subsequent interleukin-10 (IL-10) gene expression. Splenocytes from IRAK1-deficient mice fail to exhibit LPS-induced Stat3 serine phosphorylation and IL-10 gene expression yet still maintain normal IL-1beta gene expression upon LPS challenge. Mechanistically, we observe that IRAK1 modification upon LPS challenge leads to its modification, nuclear distribution, and interaction with Stat3. IRAK1 can directly use Stat3 as a substrate and cause Stat3 serine 727 phosphorylation. In addition, nuclear IRAK1 binds directly with IL-10 promoter in vivo upon LPS treatment. Atherosclerosis patients usually have elevated serum IL-10 levels. We document here that IRAK1 is constitutively modified and localized in the nucleus in the peripheral blood mononuclear cells from atherosclerosis patients. These observations reveal the mechanism for the novel role of IRAK1 in the complex Toll-like receptor signaling network and indicate that IRAK1 regulation may be intimately linked with the pathogenesis and/or resolution of atherosclerosis.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Interleukin-1 (IL-1) stimulation leads to the recruitment of interleukin-1 receptor-associated kinase (IRAK) to the IL-1 receptor, where IRAK is phosphorylated, ubiquitinated, and eventually degraded. Kinase-inactive mutant IRAK is still phosphorylated in response to IL-1 stimulation when it is transfected into IRAK-deficient cells, suggesting that there must be an IRAK kinase in the pathway. The fact that IRAK4, another IRAK family member necessary for the IL-1 pathway, is able to phosphorylate IRAK in vitro suggests that IRAK4 might be the IRAK kinase. However, we now found that the IRAK4 kinase-inactive mutant had the same ability as the wild-type IRAK4 in restoring IL-1-mediated signaling in human IRAK4-deficient cells, including NFkappaB-dependent reporter gene expression, the activation of NFkappaB and JNK, and endogenous IL-8 gene expression. These results strongly indicate that the kinase activity of human IRAK4 is not necessary for IL-1 signaling. Furthermore, we showed that the kinase activity of IRAK4 was not necessary for IL-1-induced IRAK phosphorylation, suggesting that IRAK phosphorylation can probably be achieved either by autophosphorylation or by trans-phosphorylation through IRAK4. In support of this, only the impairment of the kinase activity of both IRAK and IRAK4 efficiently abolished the IL-1 pathway, demonstrating that the kinase activity of IRAK and IRAK4 is redundant for IL-1-mediated signaling. Moreover, consistent with the fact that IRAK4 is a necessary component of the IL-1 pathway, we found that IRAK4 was required for the efficient recruitment of IRAK to the IL-1 receptor complex.
The protein kinases IRAK [IL-1 (interleukin 1) receptor-associated kinase] 1 and 4 play key roles in a signalling pathway by which bacterial infection or IL-1 trigger the production of inflammatory mediators. In the present study, we demonstrate that IRAK1 and IRAK4 phosphorylate Pellino isoforms in vitro and that phosphorylation greatly enhances Pellino's E3 ubiquitin ligase activity. We show that, in vitro, Pellino 1 can combine with the E2 conjugating complex Ubc13 (ubiquitin-conjugating enzyme 13)-Uev1a (ubiquitin E2 variant 1a) to catalyse the formation of K63-pUb (Lys63-linked polyubiquitin) chains, with UbcH3 to catalyse the formation of K48-pUb chains and with UbcH4, UbcH5a or UbcH5b to catalyse the formation of pUb-chains linked mainly via Lys11 and Lys48 of ubiquitin. In IRAK1-/- cells, the co-transfection of DNA encoding wild-type IRAK1 and Pellino 2, but not inactive mutants of these proteins, induces the formation of K63-pUb-IRAK1 and its interaction with the NEMO [NF-kappaB (nuclear factor kappaB) essential modifier] regulatory subunit of the IKK (inhibitor of NF-kappaB kinase) complex, a K63-pUb-binding protein. These studies suggest that Pellino isoforms may be the E3 ubiquitin ligases that mediate the IL-1-stimulated formation of K63-pUb-IRAK1 in cells, which may contribute to the activation of IKKbeta and the transcription factor NF-kappaB, as well as other signalling pathways dependent on IRAK1/4.
We have previously shown that the activity of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for nerve growth factor (NGF)-induced activation of NF-kappaB and cell survival ((2002) J. Biol. Chem. 277, 28010-28018). Herein we demonstrate that NGF induces co-association of IRAK with atypical protein kinase C iota (PKC) and that the iota PKC.IRAK complex is recruited to the p75 neurotrophin receptor. Recruitment of IRAK to the receptor was dependent upon the activity of the iota PKC. Moreover, transfection of kinase-dead iota PKC blocked both NGF- and IL-1-induced IRAK activation and the activity of NF-kappaB. Hence, iota PKC lies upstream of IRAK in the kappaB pathway. Examining the primary structure of IRAK, we identified three putative PKC phosphorylation sites; iota PKC selectively phosphorylated peptide 1 (RTAS) within the death domain domain at Thr66, which is highly conserved among all IRAK family members. Mutation of Thr66 to Ala impaired the autokinase activity of IRAK and reduced its association with iota PKC but not TRAF6, resulting in impaired NGF- as well as IL-1-induced NF-kappaB activation. These findings provide insight into the underlying mechanism whereby IRAK regulates the kappaB pathway and reveal that IRAK is a substrate of iota PKC.
Signal transduction by Toll-like receptor 2 (TLR2) and TLR4 requires the adaptors MyD88 and Mal (MyD88 adaptor-like) and serine/threonine kinases, interleukin-1 receptor-associated kinases IRAK1 and IRAK4. We have found that both IRAK1 and IRAK4 can directly phosphorylate Mal. In addition, co-expression of Mal with either IRAK resulted in depletion of Mal from cell lysates. This is likely to be due to Mal phosphorylation by the IRAKs because kinase-inactive forms of either IRAK had no effect. Furthermore, lipopolysaccharide stimulation resulted in ubiquitination and degradation of Mal, which was inhibited using an IRAK1/4 inhibitor or by knocking down expression of IRAK1 and IRAK4. MyD88 is not a substrate for either IRAK and did not undergo degradation. We therefore conclude that Mal is a substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of Mal. This process may serve to negatively regulate signaling by TLR2 and TLR4.
Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.
Interleukin-1 receptor-associated-kinases (IRAKs) are signal transduction mediators of the Toll/IL-1 receptor family, which comprise several transmembrane proteins involved in host defense mechanisms. Today four different human IRAKs (hu-IRAK-1, hu-IRAK-2, hu-IRAK-M, hu-IRAK-4) and two murine IRAKs (mouse pelle like kinase (mPLK) and mu-IRAK-4) have been described. Here we report the identification and characterization of murine IRAK-M (mu-IRAK-M), a mouse homologue to human IRAK-M (hu-IRAK-M). These IRAK-M molecules show 71% sequence identity, a comparable cellular expression, and functional similarities with respect to signal transduction capacity and kinase activity, suggesting functional homology in signalling in human and mouse cells.
Erratum in:
Biochem Biophys Res Commun. 304(1), 213 (2003 Apr 25)
The pleiotropic biological activities of interleukin-1 (IL-1) are mediated by its type I receptor (IL-1RI). When the ligand binds, IL-1RI initiates a signaling cascade that results in the activation of the transcription regulator nuclear factor kappa B (NF-kappa B). A protein kinase designated IRAK (IL-1 receptor-associated kinase) was purified, and its complementary DNA was molecularly cloned. When human embryonic kidney cells (cell line 293) over-expressing IL-1RI or HeLa cells were exposed to IL-1, IRAK rapidly associated with the IL-1RI complex and was phosphorylated. The primary amino acid sequence of IRAK shares similarity with that of Pelle, a protein kinase that is essential for the activation of a NF-kappa B homolog in Drosophila.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionHGNC
The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.
Evidence
2:
Inferred from Physical InteractionIntAct
Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but mechanisms for its activation and regulation remain unknown. We found here that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1; this resulted in activation of IRAK1 and facilitated its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-deficient cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant activation of IRAK1 and type I interferons in various immune diseases, controlling IRAK1 activation via inhibition of Pin1 may represent a useful therapeutic approach.
Evidence
3:
Inferred from Physical InteractionUniProtKB
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Evidence
4:
Inferred from Physical InteractionIntAct
Interleukin-1 (IL-1) receptor-associated kinase (IRAK) plays an important role in the sequential formation and activation of IL-1-induced signaling complexes. Previous studies showed that IRAK is recruited to the IL-1-receptor complex, where it is hyperphosphorylated. We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1, TAB1, and TAB2, which are preassociated on the membrane before stimulation to form the membrane-associated complex II. The formation of complex II leads to the phosphorylation of TAK1 and TAB2 on the membrane by an unknown kinase, followed by the dissociation of TRAF6-TAK1-TAB1-TAB2 (complex III) from IRAK and consequent translocation of complex III to the cytosol. The formation of complex III and its interaction with additional cytosolic factors lead to the activation of TAK1, resulting in NF-kappaB and JNK activation. Phosphorylated IRAK remains on the membrane and eventually is ubiquitinated and degraded. Taken together, the new data reveal that IRAK plays a critical role in mediating the association and dissociation of IL-1-induced signaling complexes, functioning as an organizer and transporter in IL-1-dependent signaling.
Evidence
5:
Inferred from Physical InteractionUniProtKB
Evidence for Iso 1
Our previous studies have revealed that the signaling protein BCL10 plays a major role in adaptive immunity by mediating NF-kappaB activation in the LPS/TLR4 pathway. In this study, we show that IRAK-1 acts as the essential upstream adaptor that recruits BCL10 to the TLR4 signaling complex and mediates signaling to NF-kappaB through the BCL10-MALT1-TRAF6-TAK1 cascade. Following dissociation from IRAK-1, BCL10 is translocated into the cytosol along with TRAF6 and TAK1, in a process bridged by a direct BCL10-Pellino2 interaction. RNA interference against MALT1 markedly reduced the level of NF-kappaB activation stimulated by lipopolysaccharide (LPS) in macrophages, which suggests that MALT1 plays a major role in the LPS/TLR4 pathway. MALT1 interacted with BCL10 and TRAF6 to facilitate TRAF6 self-ubiquitination in the cytosol, which was strictly dependent on the dissociation of BCL10 from IRAK-1. We show that BCL10 oligomerization is a prerequisite for BCL10 function in LPS signaling to NF-kappaB and that IRAK-1 dimerization is an important event in this process.
Evidence
6:
Inferred from Physical InteractionHGNC
The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) alpha and Mycobacterium tuberculosis. Monarch-1 reduces NFkappaB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFkappaB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/monocytic cells caused a dramatic increase in NFkappaB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFalpha, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.
Evidence
7:
Inferred from Physical InteractionIntAct
To systematically investigate innate immune signaling networks regulating production of type I interferon, we analyzed protein complexes formed after microbial recognition. Fifty-eight baits were associated with 260 interacting proteins forming a human innate immunity interactome for type I interferon (HI5) of 401 unique interactions; 21% of interactions were modulated by RNA, DNA, or LPS. Overexpression and depletion analyses identified 22 unique genes that regulated NF-κB and ISRE reporter activity, viral replication, or virus-induced interferon production. Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. Mib genes selectively controlled responses to cytosolic RNA. MIB deficiency reduced antiviral activity, establishing the role of MIB proteins as positive regulators of antiviral responses. The HI5 provides a dynamic physical and regulatory network that serves as a resource for mechanistic analysis of innate immune signaling.
Erratum in:
Immunity. 35(4), 647-8 (2011 Oct 28)
Evidence
8:
Inferred from Physical InteractionIntAct
Interleukin-1 (IL-1) receptor-associated kinases (IRAKs) are central components of Toll/IL-1 receptor (TIR) signaling pathways. In an attempt to discover novel signal transducers in TIR signaling, we identified human Pellino2 as an interaction partner of IRAK4. Pellino2 interacts with kinase-active as well as kinase-inactive IRAK1 and IRAK4. Furthermore, Pellino2 is one of the first substrates identified for IRAK1 and IRAK4. Functional studies using overexpression or RNAi knock-down of Pellino2 suggest a role of Pellino2 as a scaffolding protein similar to Pellino1. However, unlike Pellino1, Pellino2 does not seem to activate a specific transcription factor, but links TIR signaling to basic cellular processes.
Evidence
9:
Inferred from Physical InteractionIntAct
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Evidence
10:
Inferred from Physical InteractionIntAct
The interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for the IL-1-induced activation of nuclear factor kappaB and c-Jun N-terminal kinase. The goal of this study was to understand how IRAK activates the intermediate proteins TRAF6, TAK1, TAB1, and TAB2. When IRAK is phosphorylated in response to IL-1, it binds to the membrane where it forms a complex with TRAF6; TRAF6 then dissociates and translocates to the cytosol. The membrane-bound IRAK similarly mediates the IL-1-induced translocation of TAB2 from the membrane to the cytosol. Different regions of IRAK are required for the translocation of TAB2 and TRAF6, suggesting that IRAK mediates the translocation of each protein separately. The translocation of TAB2 and TRAF6 is needed to form a TRAF6-TAK1-TAB1-TAB2 complex in the cytosol and thus activate TAK1. Our results show that IRAK is required for the IL-1-induced phosphorylation of TAK1, TAB1, and TAB2. The phosphorylation of these three proteins correlates strongly with the activation of nuclear factor kappaB but is not necessary to activate c-Jun N-terminal kinase.
Evidence
11:
Inferred from Physical InteractionIntAct
Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Interleukin-1 receptor-associated-kinases (IRAKs) are signal transduction mediators of the Toll/IL-1 receptor family, which comprise several transmembrane proteins involved in host defense mechanisms. Today four different human IRAKs (hu-IRAK-1, hu-IRAK-2, hu-IRAK-M, hu-IRAK-4) and two murine IRAKs (mouse pelle like kinase (mPLK) and mu-IRAK-4) have been described. Here we report the identification and characterization of murine IRAK-M (mu-IRAK-M), a mouse homologue to human IRAK-M (hu-IRAK-M). These IRAK-M molecules show 71% sequence identity, a comparable cellular expression, and functional similarities with respect to signal transduction capacity and kinase activity, suggesting functional homology in signalling in human and mouse cells.
Erratum in:
Biochem Biophys Res Commun. 304(1), 213 (2003 Apr 25)
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level.
A series of molecular signals initiated by the binding of interleukin-1 to a receptor on the surface of a cell, and ending with regulation of a downstream cellular process, e.g. transcription.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
A series of molecular signals initiated by the binding of a lipopolysaccharide (LPS) to a receptor on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription. Lipopolysaccharides are major components of the outer membrane of Gram-negative bacteria, making them prime targets for recognition by the immune system.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Any series of molecular signals generated as a consequence of binding to a toll-like receptor where the MyD88 adaptor molecule mediates transduction of the signal. Toll-like receptors directly bind pattern motifs from a variety of microbial sources to initiate innate immune response.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Our previous studies have revealed that the signaling protein BCL10 plays a major role in adaptive immunity by mediating NF-kappaB activation in the LPS/TLR4 pathway. In this study, we show that IRAK-1 acts as the essential upstream adaptor that recruits BCL10 to the TLR4 signaling complex and mediates signaling to NF-kappaB through the BCL10-MALT1-TRAF6-TAK1 cascade. Following dissociation from IRAK-1, BCL10 is translocated into the cytosol along with TRAF6 and TAK1, in a process bridged by a direct BCL10-Pellino2 interaction. RNA interference against MALT1 markedly reduced the level of NF-kappaB activation stimulated by lipopolysaccharide (LPS) in macrophages, which suggests that MALT1 plays a major role in the LPS/TLR4 pathway. MALT1 interacted with BCL10 and TRAF6 to facilitate TRAF6 self-ubiquitination in the cytosol, which was strictly dependent on the dissociation of BCL10 from IRAK-1. We show that BCL10 oligomerization is a prerequisite for BCL10 function in LPS signaling to NF-kappaB and that IRAK-1 dimerization is an important event in this process.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Interleukin-1 receptor-associated-kinases (IRAKs) are signal transduction mediators of the Toll/IL-1 receptor family, which comprise several transmembrane proteins involved in host defense mechanisms. Today four different human IRAKs (hu-IRAK-1, hu-IRAK-2, hu-IRAK-M, hu-IRAK-4) and two murine IRAKs (mouse pelle like kinase (mPLK) and mu-IRAK-4) have been described. Here we report the identification and characterization of murine IRAK-M (mu-IRAK-M), a mouse homologue to human IRAK-M (hu-IRAK-M). These IRAK-M molecules show 71% sequence identity, a comparable cellular expression, and functional similarities with respect to signal transduction capacity and kinase activity, suggesting functional homology in signalling in human and mouse cells.
Erratum in:
Biochem Biophys Res Commun. 304(1), 213 (2003 Apr 25)
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
The process of creating protein oligomers, compounds composed of a small number, usually between three and ten, of component monomers; protein oligomers may be composed of different or identical monomers. Oligomers may be formed by the polymerization of a number of monomers or the depolymerization of a large protein polymer.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
Our previous studies have revealed that the signaling protein BCL10 plays a major role in adaptive immunity by mediating NF-kappaB activation in the LPS/TLR4 pathway. In this study, we show that IRAK-1 acts as the essential upstream adaptor that recruits BCL10 to the TLR4 signaling complex and mediates signaling to NF-kappaB through the BCL10-MALT1-TRAF6-TAK1 cascade. Following dissociation from IRAK-1, BCL10 is translocated into the cytosol along with TRAF6 and TAK1, in a process bridged by a direct BCL10-Pellino2 interaction. RNA interference against MALT1 markedly reduced the level of NF-kappaB activation stimulated by lipopolysaccharide (LPS) in macrophages, which suggests that MALT1 plays a major role in the LPS/TLR4 pathway. MALT1 interacted with BCL10 and TRAF6 to facilitate TRAF6 self-ubiquitination in the cytosol, which was strictly dependent on the dissociation of BCL10 from IRAK-1. We show that BCL10 oligomerization is a prerequisite for BCL10 function in LPS signaling to NF-kappaB and that IRAK-1 dimerization is an important event in this process.
The pleiotropic biological activities of interleukin-1 (IL-1) are mediated by its type I receptor (IL-1RI). When the ligand binds, IL-1RI initiates a signaling cascade that results in the activation of the transcription regulator nuclear factor kappa B (NF-kappa B). A protein kinase designated IRAK (IL-1 receptor-associated kinase) was purified, and its complementary DNA was molecularly cloned. When human embryonic kidney cells (cell line 293) over-expressing IL-1RI or HeLa cells were exposed to IL-1, IRAK rapidly associated with the IL-1RI complex and was phosphorylated. The primary amino acid sequence of IRAK shares similarity with that of Pelle, a protein kinase that is essential for the activation of a NF-kappa B homolog in Drosophila.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an interleukin-1 stimulus.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a lipopolysaccharide stimulus; lipopolysaccharide is a major component of the cell wall of gram-negative bacteria.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a peptidoglycan stimulus. Peptidoglycan is a bacterial cell wall macromolecule.
The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell.
Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-kappaB and AP-1. Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1beta treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.
J. Biol. Chem. 274, 19403-19410 (1999)[PubMed:10383454]
The interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for interleukin-1 (IL-1) and has later been implicated in signal transduction of other members of the Toll/IL-1 receptor family. We now report the identification and characterization of a novel IRAK-like molecule. In contrast to the ubiquitously expressed IRAK and IRAK-2, this new IRAK-like molecule is found mainly in cells of monomyeloic origin and is, therefore, designated IRAK-M. Although IRAK-M and IRAK-2 exhibit only a negligible autophosphorylation activity, they can reconstitute the IL-1 response in a 293 mutant cell line lacking IRAK. In addition, we show for the first time that members of the IRAK family are indispensable elements of lipopolysaccharide signal transduction. The discovery of IRAK-M adds another level of complexity to our understanding of signaling by members of the Toll/IL-1 receptor family.
Transmembrane receptor protein serine/threonine kinase signaling pathwaydefinition[GO:0007178]
A series of molecular signals initiated by the binding of an extracellular ligand to a receptor on the surface of the target cell where the receptor possesses serine/threonine kinase activity, and ending with regulation of a downstream cellular process, e.g. transcription.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Protein involved in immunity, any immune system process that functions in the response of an organism to a potential internal or invasive threat. The vertebrate immune system is formed by the innate immune system (composed of phagocytes, complement, antimicrobial peptides, etc) and by the adaptive immune system which consists of T- and B- lymphocytes.
Protein involved in innate immunity, an inborn defense mechanism used by organisms to defend themselves against invasion by pathogens (bacteria, fungi, viruses, etc.). Initially discovered in insects which are devoid of an adaptive immune system and rely only on innate immune reactions for their defense, this immediate response accomplishes many activities including recognition and effector functions. Recognition is mediated by broad specificity, pattern recognition, receptors which recognize many related molecular structures (e.g. polysaccharides, polynucleotides) present in microorganisms but not found in the host. The innate responses include the release of antimicrobial peptides, production of cytokines, acute- phase proteins, complement. Although many different innate immune mechanisms are deployed for host defence, a unifying theme of innate immunity is the use of germline-encoded pattern recognition receptors for pathogens or damaged self components, such as the Toll-like receptors, nucleotide-binding domain leucine-rich repeat (LRR)- containing receptors, retinoic acid-inducible gene I-like RNA helicases and C-type lectin receptors.
Protein which catalyzes the phosphorylation of serine or threonine residues on target proteins by using ATP as phosphate donor. Such phosphorylation may cause changes in the function of the target protein. Protein kinases share a conserved catalytic core common to both serine/ threonine and tyrosine protein kinases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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