Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TH17 cell immunity and autoimmune diseases.

T helper 17 (TH17) cells are heterogeneous and able to adopt pathogenic and non-pathogenic phenotypes. Identifying factors controlling pathogenic TH17 cells is of importance for their vital role in inflammation and immune-pathology. 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, yet it has no discernible effect on nonpathogenic TH17 cells. Unexpectedly, this role is independent of its canonical function in cholesterol metabolism but requires its catalytic Cys129 residue. Notably, HMGCS1 governs pTH17 cell generation and pathogenicity by leveraging an IRE1α-XBP1s-dependent ER stress response, which in turn transcriptionally activates the lineage-defining factor RORγt (encoded by Rorc). Mechanistically, HMGCS1 is located to the ER membrane, where it bound and stabilized IRE1α protein. This stabilization is achieved by preventing IRE1α's interaction with the E3 ubiquitin ligase MARCH5, thereby inhibiting its K48-linked ubiquitination and subsequent degradation. Moreover, interfering with HMGCS1 or the ER stress response in T cells impedes pTH17 immunity and mitigates autoimmune disease in vivo. Therefore, our work unveils a noncanonical axis in which HMGCS1 sustains ER stress to license pTH17 differentiation during autoimmune responses.