Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity.

ABSTRACT: Barrier tissues such as the intestine are constantly challenged by environmental stressors and must adapt to maintain integrity and prevent excessive inflammation. Although traditionally viewed as a proinflammatory effector of interferon (IFN) signaling, STAT1 is shown here to play a protective role in intestinal epithelial cells (IEC) by promoting resilience to damage and restraining IFN-induced cytotoxicity. We identify phosphorylation of threonine 748 (Thr748) on STAT1 as an evolutionarily selected adaptation-highly conserved between humans and mice-that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe colitis-induced tissue damage comparable to Stat1-deficient littermates, underscoring the critical role o

SUBMITTER: Metwally H 

PROVIDER: S-EPMC12318237 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature