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J Clin Invest. 2018 Mar 1;128(3):1125-1140. doi: 10.1172/JCI96420. Epub 2018 Feb 19.

Hypothalamic ER-associated degradation regulates POMC maturation, feeding, and age-associated obesity.

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Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA.
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Cam-Su Genomic Resource Center, Soochow University, Suzhou, Jiangsu, China.
The Warren Alpert Medical School, Department of Medicine, Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.


Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron-specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.


Cell Biology; Metabolism; Monogenic diseases; Mouse models; Protein misfolding

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