The Mechanisms to Dispose of Misfolded Proteins in the Endoplasmic Reticulum of Adipocytes
Creators: name: Wu, Alivia
Publisher: name: My University
Year: 2023
Subjects: subject: SEL1L-HRD1 ERAD
subject: Autophagy
subject: ER-phagy
subject: CERFs
subject: lipoprotein lipase
subject: protein aggregation
subject: Molecular, Cellular and Developmental Biology
subject: Science

description: Protein misfolding and aggregation in the endoplasmic reticulum (ER) contributes significantly to the pathogenesis of many devastating diseases, including α1-anti-trypsin deficiency, cystic fibrosis, diabetes, neuronal disorder, and cancer. It has been shown that cells can evolve integrated strategies to prevent the formation of potentially toxic protein aggregates in the cytosol. Within the ER, several protein quality control pathways have been identified and characterized, yet the intricate integration of these strategies to ensure the fidelity of protein folding and maturation in this organelle remains enigmatic. In this dissertation, I elucidate a series of mechanisms used by adipocytes to dispose of misfolded proteins and aggregates in the ER in vivo. First, we demonstrate (Wu et al., Nature Communications 2023) the existence of an intimate crosstalk between the two principal degradative pathways, namely ER-associated degradation (ERAD) and the selective macroautophagy known as ER-phagy, in handling misfolded proteins within the ER of adipocytes, a physiologically important cell type that regulates metabolism and energy balance. By identifying and studying the misfolding-prone protein, lipoprotein lipase (LPL), as a model substrate, we uncover a sequence of events that occur in adipocytes to dispose of misfolded proteins or aggregates in the ER: 1) under basal conditions, SEL1L-HRD1 ERAD, the most conserved mammalian ERAD branch, plays a central role in maintaining ER homeostasis by targeting misfolded substrates for proteasomal degradation; 2) in the absence of SEL1L-HRD1 ERAD, a compensatory autophagy pathway becomes active, clearing ER fragments containing misfolded proteins and limiting their aggregation within the ER; and 3) when both ERAD and autophagy functions are compromised, these ER fragments coalesce into a distinct cellular compartment termed CERFs where misfolded LPL and LPL aggregates are stored. We speculate that the formation of CERFs is cytoprotective to sequester potentially harmful protein aggregates in adipocytes lacking both ERAD and autophagy. Second, we aim to elucidate (unpublished) the mechanism underlying the crosstalk between ERAD and autophagy/ER-phagy in adipocytes in vivo. ER-phagy is mediated by a group of cargo receptor proteins, known as ER-phagy receptors. Our data indicate that the ER-phagy receptor protein, CCPG1, is a potential substrate of SEL1L-HRD1 ERAD and interacts with LPL by its luminal domain in adipocytes. Hence, we propose that SEL1L-HRD1 ERAD regulates the activity of ER-phagy towards the ER domains/substrate (e.g. LPL) by controlling the abundance of CCPG1 in the ER in adipocytes. We speculate that this might serve as a regulatory mechanism that limits excessive ER-phagy under basal conditions. In conclusion, this dissertation provides mechanistic insights into the interplay between ER protein quality control machineries under physiological settings, shedding light on the intricate network that maintains ER proteostasis. The findings presented, along with future comprehensive studies in this field, hold promise for advancing our knowledge of ER protein quality control and unveiling novel therapeutic strategies to address ER protein quality control-related pathologies.