| Project/Area Number |
19K23864
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0803:Pathology, infection/immunology, and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
METWALLY HOZAIFA 大阪大学, 免疫学フロンティア研究センター, 特任研究員 (40844246)
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | STAT1 / Threonine / Phosphorylation / Cytokines / Infection / Inflammation / phosphorylation / TLR4 / cytokines / Thr749 / Interferon / Tyr701 / threonine749 / macrophages / infection |
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| Outline of Research at the Start |
Recently, we identified STAT1 as a proinflammatory mediator downstream of TLR4 endocytosis in human macrophages independent of IFN-b-JAK/pTyr701 STAT1 signaling or NF-κB, a key proinflammatory regulator. We found that TLR4 endocytosis induces the formation of TBK1/IKKb complex, which mediates a novel phosphorylation of STAT1 at Thr749 (pThr749). Subsequently, pThr749 STAT1 binds to non-canonical DNA motif (5’...TTTGANNC...3’) at the promoter region of ARID5A (a post transcriptional regulator of IL6) and IL12B resulting in enhanced expression of IL-6 and IL-12p40.
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| Outline of Final Research Achievements |
Signal transducer and activator of transcription 1 (STAT1) regulates a wide-range of biological processes. Janus kinase (JAK)-mediated Tyr701 phosphorylation of STAT1 plays a key role in mediating interferons (IFN) signaling and antiviral response. Following binding to its ligand, the cell surface toll-like receptor (TLR) 4 is endocytosed and drives the production of IFN. Our work unveiled an alternative signaling pathway activated by endocytosed TLR4 in macrophages that contributed to the production of the proinflammatory cytokines IL-6 and IL-12p40 independently of IFN. Endocytosis of TLR4 led to noncanonical Thr749 phosphorylation, which confers STAT1 with distinct DNA binding and proinflammatory gene-regulatory properties. Our findings revolutionize the current JAK-STATs paradigm and adds a dynamic dimension to the current working framework of STAT1, which may apply to other STAT family proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
We found that STAT1 phosphorylation status affects its DNA-binding specificity and transcriptional outcome. We hope that our future studies will assist in the development of more effective therapeutic or diagnostic strategies targeting STAT1 in infection and inflammation contexts.
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