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

Arvindhan Nagarajan,Guangping Gao,Narendra Wajapeyee,Romy Kursawe,Sonia Caprio,Hai-Bin Ruan,Sanjay Bhanot,Michael J Jurczak,Gina Butrico,Gerald I Shulman,Max C Petersen,Jacques Thibodeau,Marie-Claude Bourgeois-Daigneault,Lisha Sun,Ali R Nasiri,Annie Fung,Michael R Green

doi:10.1038/ncomms12639

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.

Highlights

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling
The choice to target E3 ubiquitin ligases was guided by our recognition that despite the diverse and potent cellular functions of ubiquitination, the regulation of insulin signalling effectors by the ubiquitin code is incompletely understood but likely to participate heavily in the cellular control of insulin action
Reasoning that increased expression of the candidate gene in insulin-resistant tissue could indicate that the gene contributes to insulin resistance, we examined whether mRNA expression of any candidate gene was upregulated in high-fat diet (HFD) fed, insulin resistant mice

Summary

Introduction

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. We show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Rodent studies of global and tissue-specific INSR deletion have confirmed the severe consequences of impaired INSR function[14] Together, these studies suggest that cellular regulators of the INSR itself, rather than downstream signalling effectors, may have profound effects on cellular insulin signalling. Further work established that MARCH1 acts by regulating surface INSR levels in the basal low-insulin state, tuning cellular insulin sensitivity. This mechanism differs from that of previously reported INSR ubiquitin ligases, which are activated only after insulin stimulation

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Results

Conclusion