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

Sathi Babu Chodisetti, Adam J. Fike, Phillip P. Domeier, Stephanie L. Schell, Taryn E. Mockus, Nicholas M. Choi, Chelsea Corradetti, Baidong Hou, Hannah M. Atkins, Roberto Caricchio, Thomas Decker, Aron Lukacher, Nancy Olsen, Ziaur S.M. Rahman

Research output: Contribution to journalArticle

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Abstract

Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag–driven GC and Tfh responses in B6.Sle1b mice. By generating B cell–specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell–intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727–mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.

Original languageEnglish (US)
Pages (from-to)2641-2650
Number of pages10
JournalJournal of Immunology
Volume204
Issue number10
DOIs
StatePublished - May 15 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Chodisetti, S. B., Fike, A. J., Domeier, P. P., Schell, S. L., Mockus, T. E., Choi, N. M., Corradetti, C., Hou, B., Atkins, H. M., Caricchio, R., Decker, T., Lukacher, A., Olsen, N., & Rahman, Z. S. M. (2020). Serine phosphorylation of the STAT1 transactivation domain promotes autoreactive B cell and systemic autoimmunity development. Journal of Immunology, 204(10), 2641-2650. https://doi.org/10.4049/jimmunol.2000170