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Nat Commun. 2016 Aug 31;7:12639. doi: 10.1038/ncomms12639.

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
2
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
3
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
4
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
5
Departments of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
6
Departments of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
7
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec Canada, H3T 1J4.
8
Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
9
Isis Pharmaceuticals, Carlsbad, California 92008, USA.
10
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
11
Howard Hughes Medical Institute and Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

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.

PMID:
27577745
PMCID:
PMC5013666
DOI:
10.1038/ncomms12639
[Indexed for MEDLINE]
Free PMC Article

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