RNF26 bridges ER stress and autophagy in the clearance of MERS envelope protein.

Coronavirus envelope (E) proteins are small, highly conserved viroporins essential for virion assembly and pathogenicity. Despite extensive characterization of their ion channel activity, how host cells sense and dispose of excessive viral membrane proteins remains poorly understood. Here we show that expression of the MERS-CoV E protein triggers pronounced ER stress and autophagy activation in human cells. The E protein is selectively degraded through an RNF26-dependent autophagy-lysosome pathway, and inhibition of autophagy or loss of RNF26 function leads to E accumulation and sustained unfolded protein response. Mechanistically, RNF26, an ER-anchored E3 ubiquitin ligase, promotes RING-dependent clearance of the viral protein through an ER protein quality control-associated pathway linked to autophagy and ER stress adaptation. Disruption of this process establishes a self-amplifying ER stress-autophagy feedback loop that exacerbates proteotoxicity. These findings define a membrane homeostatic conflict between viral viroporins and the host defense machinery, and identify RNF26 as a potential therapeutic target for mitigating viroporin-induced cytotoxicity through host-directed intervention.