Salmonella Typhimurium exploits the reticulophagy/ERphagy receptor RETREG1 to promote infection.

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum, called reticulophagy/ERphagy, controls ER size and degradation of misfolded protein aggregates. RETREG1/FAM134B is an ERphagy receptor that acts by inducing ER membrane curvature and scission through oligomerization. Interestingly, RETREG1 has also been implicated in the cellular response against pathogen infection. Multiple microbes have developed strategies to inhibit ERphagy by targeting RETREG1. In a recent study, we characterized an unidentified mechanism of bacterial-mediated inhibition of ERphagy. Specifically, we found that Salmonella enterica Serovar Typhimurium, a well-known intracellular pathogen that continues to be a major cause of foodborne infections worldwide, inhibits ERphagy by specifically targeting the activity of RETREG1, leading to a pronounced increase in Salmonella burden. We show that Salmonella prevents RETREG1 oligomerization, which is required for efficient ERphagy. Conversely, Salmonella-mediated ERphagy blockage can be bypassed by promoting RETREG1 oligomerization, which recovers ERphagy levels. Salmonella infection also decreases RETREG1 phosphorylation and acetylation, previously reported to be requisite steps in RETREG1-driven ERphagy. Furthermore, in vivo analysis of retreg1 knockout mice infected with Salmonella reveals increased intestinal damage and bacterial levels. Our results provide insights into the interplay between ERphagy and bacterial infection, highlighting a key role for RETREG1 in innate immunity.