The role of ER-associated degradation and ER-phagy in health and disease

The endoplasmic reticulum (ER) is a major cellular organelle for the synthesis and folding of secretory and transmembrane proteins, whose proper function underpins organellar homeostasis, proper tissue function, and organismal physiology. Protein quality control (PQC) systems at the ER include the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy, which monitor ER homeostasis and contribute to protein refolding, sequestration, or degradation. ERAD prevents the accumulation of misfolded or orphan proteins that would otherwise be toxic. By controlling the degradation of these proteins, ERAD performs a core function in governing adaptation to proteotoxic stress. ERAD also regulates the abundance of folding-competent proteins as a means to fine-tune key physiological processes. Among its complex regulatory activities, ERAD controls cellular processes such as lipid homeostasis, calcium flux, and cell fate decisions, which are all required for the maintenance of organelle homeostasis. Highlighting its importance, dysregulation of ERAD often results in devastating diseases. Here, we discuss the molecular and mechanistic understanding of protein quality and quantity control by ERAD and its interface with ER-phagy, as well as other cellular stress programs. The implications of ERAD and its associated regulatory arms for cellular homeostasis, its effects on health and disease, and current therapeutic approaches are discussed.