MARCH1 Regulates Insulin Sensitivity by Controlling Cell Surface Insulin Receptor Levels

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Sep 1

PMID 27577745

Citations 46

Authors

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

Narendra Wajapeyee

Affiliations

Soon will be listed here.

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.

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