New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation

Abstract

Many human diseases are associated with mutations causing protein misfolding and aggregation in the endoplasmic reticulum (ER). ER-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. However, despite years of effort, the physiological role of ERAD in vivo remains largely unknown. Several recent studies have reported intriguing phenotypes of mice deficient for ERAD function in specific cell types. These studies highlight that mammalian ERAD has been designed to perform a wide-range of cell-type-specific functions in vivo in a substrate-dependent manner.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

“…This conclusion underscores the importance of an improved understanding of cell type-specific ERAD function in the pathogenesis of many human diseases. While ERAD has largely been studied as a mechanism for clearance of misfolded model substrates (11,12), our findings uncover what we believe to be a novel role of ERAD in the folding of at least a subset of prohormones in endocrine cells under physiological and pathological contexts. Endocrine cells such as AVP neurons are committed and specifically adapted to make specialized prohormones at high levels; however, such high levels may make independent mouse models demonstrate both the significance of ERAD in normal physiology and the potential significance of this pathway in human disease pathogenesis (11,12).…”

“…Recent studies in mouse models have suggested varying effects of ERAD on the fate of different substrates (11). For example, IRE1α, which is a Sel1L-Hrd1 ERAD substrate in many cell types (20), accumulates in the ER but remains functional to sense misfolded ER proteins in ERAD-deficient cells.…”

“…Misfolded proteins in the ER are targeted for proteasomal degradation by a highly conserved quality-control mechanism known as ER-associated degradation (ERAD) (11,12). Among over a dozen E3 ligases in mammalian ERAD, the hydroxymethylglutaryl-CoA reductase degradation protein 1 (Hrd1) is a principal ER-resident E3 ligase that forms a complex with the ER-resident Peptide hormones are crucial regulators of many aspects of human physiology.…”

“…To investigate the role of Sel1L-Hrd1 ERAD in AVP neurons, we generated AVP neuron-specific Sel1L-KO (Sel1L AVP ) mice by crossing Sel1L fl/fl mice with AVP neuron-specific suppressor-enhancer of lin-12-like (Sel1L, also known as mammalian Hrd3) (13)(14)(15)(16)(17)(18)(19). Together, this complex is responsible for the degradation of a subset of misfolded proteins in the ER (11,12). Like its yeast counterpart Hrd3p (14), mammalian Sel1L is required for the stability of Hrd1 (20) and may both directly recruit substrates to Hrd1 (21) and regulate Hrd1 activity (22).…”

“…Germline Sel1L or Hrd1 deficiency is embryonically lethal in mice (23,24), and acute global loss of Sel1L or Hrd1 in adult mice leads to premature death within 2 to 3 weeks (20,23), suggesting that Sel1L and Hrd1 are indispensable for both development and postnatal survival (11). Recent studies of cell type-specific Sel1L-Hrd1 deficiency in adipocytes (25,26), B cells (27), and colonic epithelium (21) have delineated the physiological importance of ERAD in these various tissues and identified several endogenous substrates (11), including IRE1α of the unfolded protein response (UPR) in many cell types (20); lipoprotein lipase and PGC1β in adipocytes (25,26); and pre-B cell receptor in developing B cells (27). However, the role of ERAD in neuroendocrine cells has not been explored.…”