Interaction between quality control systems for ER protein folding and RNA biogenesis

The endoplasmic reticulum (ER) is the intracellular organelle responsible for the synthesis, folding and assembly of proteins destined for secretion and the endomembrane system of the cell. ER quality control (ERQC) is an intensively studied surveillance mechanism that selectively degrades misfolded proteins to ensure that only properly folded proteins exit the ER en route to the Golgi compartment. Proper protein folding is indispensable for the differentiation and function of cells that secrete high levels of protein and defects in protein folding are implicated in many pathologies, including metabolic, genetic, neurodegenerative and inflammatory diseases. Accumulation of misfolded proteins in the ER activates an adaptive set of signaling pathways, collectively known as the unfolded protein response (UPR), to resolve protein misfolding and restore ER homeostasis. Nonsense-mediated RNA decay (NMD) is an RNA surveillance system that selectively degrades nascent mRNAs containing premature termination codons (PTCs). Recently, we used a genetic screen to identify genes that interact with UPR signaling in C. elegans. These studies identified NMD-associated genes that are required for ER protein folding homeostasis. These findings link the quality control systems required for ER protein folding and RNA biogenesis, provide new insights into mechanisms of ERQC and have implications on diseases of ER dysfunction and therapeutic approaches based on NMD inhibition. Here, we discuss the biological significance of these findings and future directions for study.