STAT6 plays a prominent role in adaptive immunity by transducing signals from extracellular cytokines. We now show that STAT6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger STING (also named MITA/ERIS) to recruit STAT6 to the endoplasmic reticulum, leading to STAT6 phosphorylation on Ser(407) by TBK1 and Tyr(641), independent of JAKs. Phosphorylated STAT6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. Virus-induced STAT6 activation is detected in all cell-types tested, in contrast to the cell-type specific role of STAT6 in cytokine signaling, and Stat6(-/-) mice are susceptible to virus infection. Thus, STAT6 mediates immune signaling in response to both cytokines at the plasma membrane, and virus infection at the endoplasmic reticulum.
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 InteractionIntAct
STAT6 plays a prominent role in adaptive immunity by transducing signals from extracellular cytokines. We now show that STAT6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger STING (also named MITA/ERIS) to recruit STAT6 to the endoplasmic reticulum, leading to STAT6 phosphorylation on Ser(407) by TBK1 and Tyr(641), independent of JAKs. Phosphorylated STAT6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. Virus-induced STAT6 activation is detected in all cell-types tested, in contrast to the cell-type specific role of STAT6 in cytokine signaling, and Stat6(-/-) mice are susceptible to virus infection. Thus, STAT6 mediates immune signaling in response to both cytokines at the plasma membrane, and virus infection at the endoplasmic reticulum.
RNA polymerase II core promoter sequence-specific DNA bindingdefinition[GO:0000979]‹silver
Interacting selectively and non-covalently with the regulatory region composed of the transcription start site and binding sites for transcription factors of the RNA polymerase II basal transcription machinery.
IEAOrtholog Compara
Sequence-specific DNA binding transcription factor activitydefinition[GO:0003700]‹silver
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
Conveys a signal across a cell to trigger a change in cell function or state. A signal is a physical entity or change in state that is used to transfer information in order to trigger a response.
A series of molecular signals initiated by the binding of a cytokine to a receptor on the surface of a cell, and ending with regulation of a downstream cellular process, e.g. transcription.
The multiplication or reproduction of mammary gland epithelial cells, resulting in the expansion of a cell population. Mammary gland epithelial cells make up the covering of surfaces of the mammary gland. The mammary gland is a large compound sebaceous gland that in female mammals is modified to secrete milk.
The process in which anatomical structures of the mammary gland are generated and organized. Morphogenesis refers to the creation of shape. The mammary gland is a large compound sebaceous gland that in female mammals is modified to secrete milk.
IEAOrtholog Compara
Negative regulation of transcription from RNA polymerase II promoterdefinition[GO:0000122]‹silver
Any process that stops, prevents, or reduces the frequency, rate or extent of transcription from an RNA polymerase II promoter.
J. Biol. Chem. 271, 25555-25561 (1996)[PubMed:8810328]
This study addresses the function of STAT6 in interleukin-4-stimulated gene expression. A specific STAT6 DNA-binding target site has been identified in the promoter of the interleukin-4 receptor gene, and STAT6 is shown to be involved in mediating activation of gene expression via this site. STAT6 can mediate transcription of a heterologous reporter gene construct containing the interleukin-4 receptor STAT6 binding site. In addition, evidence is provided that demonstrates a distinct effect of STAT6 DNA binding specificity on transcriptional regulation since transcription was not stimulated from a competent but different DNA binding site. To confirm the role of STAT6 in gene activation, STAT6 mutant proteins were generated and analyzed for their ability to function in interleukin-4-induced transcription. Although the interleukin-2 gamma chain receptor subunit has been demonstrated to be a component of the interleukin-4 receptor, it is not required for specific gene activation.
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.
J. Biol. Chem. 275, 14255-14259 (2000)[PubMed:10747856]
Interleukin-4 (IL-4) is a cytokine that plays a crucial role in the pathophysiology of asthma and allergic diseases. IL-4-induced gene expression is largely mediated through the activation of the latent transcription factor STAT6. We identified a STAT6 mutant (STAT6VT)) that is activated independently of IL-4 stimulation. STAT6VT carries two amino acid changes in the SH2 domain that affect the overall structure and stability of the monomeric and dimeric protein. When overexpressed in mammalian cells, STAT6VT undergoes tyrosine phosphorylation, binds DNA, and activates transcription in the absence of IL-4 stimulation. Using the Jak1- and Jak3-deficient fibroblast line U4A, we demonstrate that phosphorylation is mediated by an IL-4-independent tyrosine kinase that is not able to activate the wild-type STAT6 protein. These results suggest that small changes in STAT6 could result in hyperactivation of the protein and constitutive expression of STAT6-dependent genes. Such a mutation, if found in vivo, could cause genetic predisposition for atopic diseases.
The process in which a CD4-positive, alpha-beta T cell becomes committed to becoming a T-helper 1 cell, a CD4-positive, alpha-beta T cell specialized to promote immunological processes often associated with resistance to intracellular bacteria, fungi, and protozoa, and pathological conditions such as arthritis.
Protein involved in the transfer of genetic information from DNA to messenger RNA (mRNA) by DNA-directed RNA polymerase. In the case of some RNA viruses, protein involved in the transfer of genetic information from RNA to messenger RNA (mRNA) by RNA-directed RNA polymerase.
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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