Unconventional role of HMGCS1 in driving pathogenic-Th17 cell immunity and autoimmune diseases

Identifying factors controlling pathogenic-Th17 cells is of importance, for their vital role in inflammation and immune-pathology. While intricate ER stress signals have been implicated in T cell biology, its role in Th17 cells remain poorly understood. Here, we demonstrated that HMGCS1, a cholesterol biosynthesis precursor enzyme, was highly induced by inflammatory cytokines and preferentially expressed by pathogenic-Th17 cells in vitro and in vivo. HMGCS1 specifically dictated pathogenic-Th17 cell differentiation and augmented autoimmune diseases. Nonetheless, HMGCS1 role in pathogenic-Th17 cells was independently of cholesterol metabolism but necessitated its catalytic Cys129 residue. Notably, HMGCS1 leveraged IRE1a-XBP1s-dependent ER stress response which was essential for pTh17 cell generation and pathogenicity by transcriptionally activating Rorc loci. Mechanistically, HMGCS1 located to the ER membrane, where it bound and stabilized IRE1a protein via restraining IRE1a interaction with K48-linked ubiquitination-dependent E3 ligase MARCH5. Of note, interfering HMGCS1 and ER stress impeded pathogenic-Th17 immunity and mitigated autoimmune diseases. Therefore, our work reveals a non-canonical axis wherein HMGCS1 sustains ER stress to license pTh17 cell differentiation during autoimmune responses.