A Central Role of SEL1L-HRD1 ERAD in LPL Maturation in Adipocytes SUMMARY My laboratory has a long-standing interest in protein folding and degradation within the endoplasmic reticulum (ER) by defining the (patho-)physiological importance of mammalian ER quality-control machineries in vivo. ER- associated degradation (ERAD) is the principal protein quality-control mechanism responsible for targeting misfolded proteins in the ER for cytosolic proteasomal degradation. The SEL1L-HRD1 protein complex represents the most conserved branch of ERAD from yeast to humans. We recently showed that SEL1L-HRD1 ERAD protein complex coordinates with autophagy, or specifically ER-phagy, in adipocytes to ensure the maturation of lipoprotein lipases (LPL), a key enzyme involved in lipoprotein hydrolysis and systemic lipid partitioning, in the ER. ERAD degrades misfolded nascent LPL in the ER and, when ERAD is impaired, LPL forms aggregates and sequestered in ER fragments which are subsequently cleared by ER-phagy. When ERAD and autophagy are both compromised, ER fragments containing LPL aggregates spatially coalesce into a distinct cellular architecture termed Coalescence of ER Fragments (CERFs). Proteomics screens identify lipoprotein lipase (LPL) and ER chaperone BiP as principal components of CERFs. Hence, our data point to a synergism between ERAD and autophagy in adipocytes; however, the underlying molecular mechanism remains vague. Our proteomics screens for SEL1L and LPL interactors both identified CCPG1, an ER-resident ER-phagy receptor, as a top hit. Strikingly, our preliminary data showed that CCPG1 interacts with LPL and is an ERAD substrate, i.e. degraded by SEL1L-HRD1 ERAD, suggesting that CCPG1 may link ERAD to ER-phagy of LPL aggregates. Demonstrating the clinical relevance, we further showed that disease-causing LPL variants in patients with familial hypertriglyceridemia are retained intracellularly as large aggregates in the absence of ERAD. We will test the hypothesis that SEL1L-HRD1 ERAD regulates ER-phagy activity via ER-phagy receptor CCPG1 to maintain ER homeostasis and ensure the maturation of secreted proteins such as LPL in adipocytes. This model expands the current paradigm in ER biology by placing SEL1L-HRD1 ERAD at the center of cellular quality-control function and identifying new LPL regulators. Using various mouse models, we will (1) determine whether SEL1L-HRD1 ERAD regulates ER-phagy of LPL aggregates via CCPG1 in adipocytes; and (2) delineate the pathological importance of SEL1L-HRD1 ERAD and CCPG1-mediated ER-phagy in the pathogenicity of LPL disease mutants and its underlying mechanism. This study will provide unprecedented insights into the role of various key ER quality control machineries in regulating LPL biology in adipocytes. RELEVANCE TO HUMAN HEALTH: LPL deficiency is a rare genetic disorder that can lead to abnormal accumulation of triglycerides in the blood and an increased risk of diabetes and cardiovascular disease. T...