ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

TLDR

ERIS, also known as STING or MITA, is an endoplasmic reticulum–localized protein. The study identifies and characterizes ERIS as a potent type I interferon stimulator involved in sensing cytosolic RNA and dsDNA. The ER retention/retrieval sequence RIR is essential for ER localization and protein integrity, and ERIS dimerization—induced by coumermycin—triggers rapid, robust type I IFN production, underscoring dimerization as key for self‑activation.

Abstract

We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.