Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons
Sang-Hyeon Mun,
Chang-Seok Lee,
Hyun Jin Kim,
Jiye Kim,
Haena Lee,
Jihye Yang,
Sin-Hyeog Im,
Joung-Hun Kim,
Je Kyung Seong,
Cheol-Sang Hwang
Affiliations
Sang-Hyeon Mun
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea
Chang-Seok Lee
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea
Hyun Jin Kim
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea
Jiye Kim
Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, South Korea; Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea; Interdisciplinary Program for Bioinformatics, Program for Cancer Biology and BIO-MAX/N-Bio Institute, Seoul National University, Seoul 08826, South Korea
Haena Lee
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea
Jihye Yang
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea
Sin-Hyeog Im
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea; Institute of Convergence Science, Yonsei University, Seoul 03722, South Korea; ImmunoBiome, Inc, Pohang 37666, Republic of Korea
Joung-Hun Kim
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea; Institute of Convergence Science, Yonsei University, Seoul 03722, South Korea
Je Kyung Seong
Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, South Korea; Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea; Interdisciplinary Program for Bioinformatics, Program for Cancer Biology and BIO-MAX/N-Bio Institute, Seoul National University, Seoul 08826, South Korea
Cheol-Sang Hwang
Department of Life Sciences, Korea University, Seoul 02841, South Korea; Corresponding author
Summary: The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment develop metabolic disorders. However, the existence, metabolic fate, and functional outcomes of cytosol-retained POMC remain unclear. Here, we show that SP-uncleaved POMC is produced in the cytosol of POMC neuronal cells, thus inducing ER stress and ferroptotic cell death. Mechanistically, the cytosol-retained POMC sequesters the chaperone Hspa5 and subsequently accelerates degradation of the glutathione peroxidase Gpx4, a core regulator of ferroptosis, via the chaperone-mediated autophagy. We also show that the Marchf6 E3 ubiquitin ligase mediates the degradation of cytosol-retained POMC, thereby preventing ER stress and ferroptosis. Furthermore, POMC-Cre-mediated Marchf6-deficient mice exhibit hyperphagia, reduced energy expenditure, and weight gain. These findings suggest that Marchf6 is a critical regulator of ER stress, ferroptosis, and metabolic homeostasis in POMC neurons.
