Corilagin regulates antigen processing and presentation by directly binding to inhibit ERAP1

ERAP1 is a critical aminopeptidase that acts as the final "editor" of endogenous antigen peptides in the endoplasmic reticulum, playing a key role in the MHC-I-mediated antigen processing and presentation pathway. It has become a novel target for a broad class of severe autoimmune diseases, referred to as "MHC-I-opathy," as well as for tumor immune evasion. Here, we report the discovery of a food-derived natural product inhibitor, Corilagin, with a novel scaffold that directly interacts with ERAP1, identified through high-throughput screening. Corilagin is one of the few reported ERAP1 inhibitors that exhibit both high activity and selectivity. Biochemical experiments demonstrate that Corilagin directly binds to the ERAP1 active site in a substrate-competitive inhibition mode. Structurally, Corilagin may preferentially bind to the S1 pocket and more distal sites of ERAP1. In a cell model of ankylosing spondylitis mediated by HLA-B27 antigen presentation, Corilagin was found to reverse ERAP1-induced endoplasmic reticulum stress and the disrupted antigen presentation phenotype. This suggests that Corilagin has potential therapeutic value for "MHC-I-opathy" related autoimmune diseases and tumor immune evasion. In conclusion, our findings provide a novel structural basis for the design of ERAP1 inhibitors and reveal a rare direct target for Corilagin within the human body.