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Global riactice Leader's in Brain Science

10/17 (Wed) 16:00 Regular Seminar
Name : 관리자 | Date : 2018.10.11 11:38 | Views : 979

Title: The role of hypothalamic Sel1L-Hrd1 ER-associated degradation (ERAD) in feeding and energy balance


Speaker: Geun Hyang Kim, Ph.D., Department of Molecular & Integrative Physiology, University of Michigan Medical School (Host : Eun-Kyoung Kim)


Time: 16:00, October 17 (Wed), 2018
        

Venue: Room 114, Building E4, DGIST


Abstract : 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. Recently, we demonstrated that the protein complex of ERAD, a critical protein quality-control system, plays an important role in prohormone processing and maturation, thereby controlling feeding and energy balance. Strikingly, mice with POMC neuron–specific ERAD deficiency developed age-associated obesity on normal chow diet due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 ERAD complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC. This ensures that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F (a single POMC cysteine-to-phenylalanine mutation at position 28) mutant evades ERAD and forms high molecular-weight aggregates. This finding fills a gap in knowledge demonstrating that POMC-C28F is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans. Overall, 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.


Person in charge : Sora Lee


Contact: srlee@dgist.ac.kr, 053)785-6102

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