Serine phosphorylation of the STAT1 transactivation domain promotes autoreactive B cell and systemic autoimmunity development

Abstract

Abstract Although STAT1 tyrosine-701 phosphorylation (STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (STAT1-pS727) during autoimmune and anti-pathogen responses remains unclear. Here we report that STAT1-pS727 promotes autoimmune antibody-forming cell (AFC) and germinal center (GC) responses, driving systemic lupus erythematosus (SLE) development. STAT1-pS727, however, is not required for GC and antibody responses to foreign-antigens including pathogens or gut microbiota. STAT1-pS727 plays an important B cell-intrinsic role in driving autoimmunity. Transcriptomic analysis of B cells from TLR7-accelerated SLE-prone mice reveals STAT1-pS727-mediated gene regulation of cellular pathways known to be involved in autoimmune GC and AFC responses. Mechanistically, TLR7 activation in B cells induces STAT1-pS727 and during autoimmune responses TLR7 signaling converges with IFNγ-STAT1 signaling in B cells by recruiting STAT1 into the MyD88 signaling complex. Together, we identify previously unappreciated differential regulation of autoimmune and anti-pathogen responses by STAT1-pS727, and implicate STAT1-pS727 as a therapeutic target for SLE.