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

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.