Threonine Phosphorylation and the Yin and Yang of STAT1: Phosphorylation-Dependent Spectrum of STAT1 Functionality in Inflammatory Contexts

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 18; p. 1531
• Main Authors: Elbrashy, Maha M, Metwally, Hozaifa, Sakakibara, Shuhei, Kishimoto, Tadamitsu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.09.2024; MDPI
• Subjects: Amino acids; Analysis; Animals; Anti-DNA antibodies; Autoantibodies; Autoimmune diseases; Autoimmunity; B cells; Belimumab; Biological response modifiers; Creatinine; Females; Genetic engineering; Genetically modified organisms; Genomes; Immune response; Immunoglobulin G; Inflammation; Inflammation - metabolism; Inflammation - pathology; Innate immunity; Interferon; interferons; Kidney diseases; Kinases; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis; Nucleic acids; Phosphorylation; Pristane; Proteins; Signal Transduction; STAT1; Stat1 protein; STAT1 Transcription Factor - metabolism; Survival; Systemic lupus erythematosus; Terpenes; Threonine; Threonine - metabolism; Tyrosine; Massachusetts; Japan; Chicago Illinois; United States > US; Germany; interferons; autoimmunity; STAT1; inflammation; threonine; lupus; phosphorylation
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13181531

Threonine phosphorylation promotes inflammatory functions of STAT1 while restricting its interferon (IFN) signaling in innate immune responses. However, it remains unclear whether the restriction of STAT1-mediated IFN signaling conferred by threonine phosphorylation is a ubiquitous mechanism or one that is context-dependent. To address this, we utilized pristane-induced lupus, a prototype IFN-driven systemic autoimmune disease model characterized by the production of high-titer autoantibodies against nucleic acid-associated antigens. Through genetic and biochemical assays, we demonstrate that Thr748 phosphorylation is dispensable for STAT1 functionality in pristane-induced lupus. Genetically engineered mice expressing the phospho-deficient threonine 748-to-alanine (T748A) mutant STAT1 exhibited similar survival rates, high titers of anti-dsDNA IgG, and nephritis compared to their wild-type littermates. In sharp contrast, STAT1 deficiency protected mice against pristane-induced lupus, as evidenced by increased survival, low titers of anti-dsDNA IgG, and less severe nephritis in the STAT1 knockout mice compared to their T748A littermates. Our study suggests a phosphorylation-dependent modularity that governs the spectrum of STAT1 functionality in inflammatory contexts: IFN phospho-tyrosine-dependent and inflammatory phospho-threonine-dependent, with Thr748 phosphorylation driving selective inflammatory activities, particularly those not driven by the canonical JAK pathway. From a broader perspective, our findings provide deeper insights into how distinct phosphorylation events shape the combinatorial logic of signaling cassettes, thereby regulating context-dependent responses.