The Role of SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation in Hypothalamic Regulation of Metabolism and Beyond
dc.contributor.author | Mao, Hancheng | |
dc.date.accessioned | 2024-05-22T17:20:49Z | |
dc.date.available | 2024-05-22T17:20:49Z | |
dc.date.issued | 2024 | |
dc.date.submitted | 2024 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/193179 | |
dc.description.abstract | The endoplasmic reticulum (ER) is a vital organelle responsible for several aspects of cell function and signaling, including protein synthesis, folding, modification, trafficking and quality control; lipid synthesis and transportation; calcium storage and signaling. Upon physiological stimulus and environmental stress, ER protein homeostasis (proteostasis) can be challenged and disturbed where proteins in the ER misfold and even aggregate, leading to proteotoxicity that threatens function and survival of the cells. To maintain ER proteostasis, numerous ER quality control systems have evolved, including unfolded protein response (UPR), ER-associated degradation (ERAD) and autophagy (ER-phagy). In particular, ERAD is a constitutively active machinery that efficiently clears misfolded ER proteins by targeting them for proteasomal degradation. Among multiple identified ERAD complexes, the Suppressor/enhancer of Lin-12 Like-HMG-coA reductase degradation (SEL1L-HRD1) ERAD complex is most conserved across mammals and comprehensively investigated. To date, the pathophysiological importance of SEL1L-HRD1 ERAD has been well demonstrated in a cell type-specific and substrate-dependent manner. However, it remains largely unknown the role of SEL1L-HRD1 in heterogenous cell populations in central nervous system (CNS) and how this complex engages in organismal health and disease via maintaining proteostasis in CNS. This dissertation provides explorations and findings in the role of hypothalamic SEL1L-HRD1 in metabolic regulation, as a good start for filling the knowledge gap. The ER proteostasis of hypothalamic neurons is indispensable for neuronal activity and function to mediate organismal energy balance in response to altering nutritional status. Interestingly, we observed, upon acute HFD feeding for one week, a transient induction of SEL1L-HRD1 protein abundance in hypothalamic neurons, including pro-opiomelanocortin (POMC) neurons as key regulators of food intake and energy expenditure. Notably, deficiency of SEL1L in POMC neurons significantly predisposed mice to diet-induced obesity (DIO) due to hyperphagia. Mechanistically, the increased food intake was attributed to leptin resistance in POMC neurons deficient in SEL1L-HRD1, independent of UPR. Further investigation provided evidence that SEL1L-HRD1 controls leptin signaling by maintaining maturation and membrane display of leptin receptor long isoform (LepRb). Particularly, SEL1L-HRD1 ensured efficient degradation of misfolded LepRb, and the deficiency of SEL1L-HRD1 rendered accumulation of misfolded LepRb aggregates, interfering with folding and maturation of nascent LepRb. Hence, SEL1L-HRD1 ERAD regulates leptin signaling via LepRb in a substrate dependent manner. In addition to demonstrating the role of hypothalamic SEL1L-HRD1 in metabolic regulation, we also identified and characterized astrotactin1 (ASTN1) as a bona fide endogenous substrate of SEL1L-HRD1 that mediates neuronal plasticity and contact with glial cells and closely associated with neurodevelopmental disorders. Together, these findings underscore the significance of SEL1L-HRD1 ERAD in CNS, from hypothalamus and beyond. | |
dc.language.iso | en_US | |
dc.subject | SEL1L-HRD1 Endoplasmic Reticulum Associated Degradation (ERAD) | |
dc.subject | Unfolded Protein Response (UPR) | |
dc.subject | Leptin Signaling and Receptor (LepRb) | |
dc.subject | Diet-associated Obesity and Pathogenesis | |
dc.subject | Hypothalamus and Hypothalamic POMC neurons | |
dc.subject | Astrotactin-1 (ASTN1) as SEL1L-HRD1 ERAD Substrate | |
dc.title | The Role of SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation in Hypothalamic Regulation of Metabolism and Beyond | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | |
dc.description.thesisdegreediscipline | Molecular and Integrative Physiology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Arvan, Peter | |
dc.contributor.committeemember | Qi, Ling | |
dc.contributor.committeemember | Klionsky, Daniel J | |
dc.contributor.committeemember | Elias, Carol | |
dc.subject.hlbsecondlevel | Physiology | |
dc.subject.hlbtoplevel | Science | |
dc.contributor.affiliationumcampus | Ann Arbor | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/193179/1/hancheng_1.pdf | |
dc.identifier.doi | https://dx.doi.org/10.7302/22824 | |
dc.identifier.orcid | 0000-0003-2546-6774 | |
dc.identifier.name-orcid | Mao, Hancheng; 0000-0003-2546-6774 | en_US |
dc.working.doi | 10.7302/22824 | en |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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