Inhibition of the oligosaccharyl transferase in Caenorhabditis elegans that compromises ER proteostasis suppresses p38-dependent protection against pathogenic bacteria

Abstract

The oligosaccharyl transferase (OST) protein complex mediates the N-linked glycosylation of substrate proteins in the endoplasmic reticulum (ER), which regulates stability, activity, and localization of its substrates. Although many OST substrate proteins have been identified, the physiological role of the OST complex remains incompletely understood. Here we show that the OST complex in C. elegans is crucial for ER protein homeostasis and defense against infection with pathogenic bacteria Pseudomonas aeruginosa (PA14), via immune-regulatory PMK-1/p38 MAP kinase. We found that genetic inhibition of the OST complex impaired protein processing in the ER, which in turn up-regulated ER unfolded protein response (UPRER). We identified vitellogenin VIT-6 as an OST-dependent glycosylated protein, critical for maintaining survival on PA14. We also showed that the OST complex was required for up-regulation of PMK-1 signaling upon infection with PA14. Our study demonstrates that an evolutionarily conserved OST complex, crucial for ER homeostasis, regulates host defense mechanisms against pathogenic bacteria. Author summary N-linked glycosylation is essential for the function of various proteins, but its effects on physiology at an organism level remain poorly understood. Using the roundworm Caenorhabditis elegans, we show that the oligosaccharyl transferase (OST) complex, which mediates the N-glycosylation of substrate proteins in the ER, reduces susceptibility to pathogenic bacteria, Pseudomonas aeruginosa. We find that OST enhances defense against P. aeruginosa via maintenance of ER unfolded protein response (UPRER) and up-regulation of cytosolic p38 MAP kinase signaling. Our findings propose an intriguing model for the organellar crosstalk between the ER and the cytosol in host defense mechanisms. Because the OST complex components are highly conserved among eukaryotes, our study on the regulation of cellular signaling and C. elegans physiology by the OST complex will provide an insight into the function of its mammalian counterpart.