MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels

Arvindhan Nagarajan, Max C. Petersen, Ali R. Nasiri, Gina Butrico, Annie Fung, Hai-Bin Ruan, Romy Kursawe, Sonia Caprio, Jacques Thibodeau, Marie-Claude Bourgeois-Daigneault, Lisha Sun, Guangping Gao, Sanjay Bhanot, Michael J. Jurczak, Michael R. Green, Gerald I. Shulman () and Narendra Wajapeyee ()
Additional contact information
Arvindhan Nagarajan: Yale University School of Medicine, New Haven, Connecticut 06510, USA
Max C. Petersen: Howard Hughes Medical Institute, Yale University School of Medicine
Ali R. Nasiri: Yale University School of Medicine
Gina Butrico: Yale University School of Medicine
Annie Fung: Yale University School of Medicine
Hai-Bin Ruan: Yale University School of Medicine
Romy Kursawe: Yale University School of Medicine
Sonia Caprio: Yale University School of Medicine
Jacques Thibodeau: Infectiologie et Immunologie, Université de Montréal
Marie-Claude Bourgeois-Daigneault: Infectiologie et Immunologie, Université de Montréal
Lisha Sun: Yale University School of Medicine, New Haven, Connecticut 06510, USA
Guangping Gao: Gene Therapy Center, University of Massachusetts Medical School
Sanjay Bhanot: Isis Pharmaceuticals
Michael J. Jurczak: University of Pittsburgh
Michael R. Green: Cell and Cancer Biology, University of Massachusetts Medical School
Gerald I. Shulman: Howard Hughes Medical Institute, Yale University School of Medicine
Narendra Wajapeyee: Yale University School of Medicine, New Haven, Connecticut 06510, USA

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12639

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