title: MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.
abstract: Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target.
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Arvindhan
authors: A
authors: Nagarajan
authors: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Max C
authors: MC
authors: Petersen
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Ali R
authors: AR
authors: Nasiri
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Gina
authors: G
authors: Butrico
authors: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Annie
authors: A
authors: Fung
authors: Departments of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Hai-Bin
authors: 0000-0002-3858-1272
authors: HB
authors: Ruan
authors: Departments of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Romy
authors: R
authors: Kursawe
authors: Departments of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Sonia
authors: S
authors: Caprio
authors: Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec Canada, H3T 1J4.
authors: Jacques
authors: J
authors: Thibodeau
authors: Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec Canada, H3T 1J4.
authors: Marie-Claude
authors: MC
authors: Bourgeois-Daigneault
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Lisha
authors: L
authors: Sun
authors: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Guangping
authors: G
authors: Gao
authors: Isis Pharmaceuticals, Carlsbad, California 92008, USA.
authors: Sanjay
authors: S
authors: Bhanot
authors: Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors: Michael J
authors: MJ
authors: Jurczak
authors: Howard Hughes Medical Institute and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Michael R
authors: 0000-0003-3017-3298
authors: MR
authors: Green
authors: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Gerald I
authors: 0000-0003-1529-5668
authors: GI
authors: Shulman
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Narendra
authors: N
authors: Wajapeyee
mesh_terms: D052436:Adipose Tissue, White / Q000473:pathology; D000293:Adolescent; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology* / Q000628:therapy; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D007328:Insulin; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; C545340:MARCH1 protein, mouse; C528121:MARCHF1 protein, human; D044767:Ubiquitin-Protein Ligases; C435941:INSR protein, human; D011972:Receptor, Insulin