Unveiling Novel STAT1 Activation Expands its Anti-viral Role into Host Defense Against Bacterial Pathogens

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23864
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: Osaka University
• 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)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: STAT1 / Threonine / Phosphorylation / Cytokines / Infection / Inflammation

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.

Free Research Field

Immunology

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.