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.
Bibliographical noteFunding Information:
We gratefully acknowledge grants from the National Institutes of Health: R01 DK-40936, U24 DK-059635, P30 DK-45735, P30 DK-34989 and UL1 TR-000142 (G.I.S.); R21CA197758-01 (N.W.), R21CA191362-01 (N.W.) R01CA200919-01 (N.W.) and R01CA19656601A1 (N.W.), R01 GM033977 (M.R.G); T32 GM-007205, and F30 DK-104596 (M.C.P.); and K01 DK-099402 (M.J.J.). N.W. is also supported by a Research Scholar Grant from American Cancer Society (128347-RSG-15-212-01-TBG) and a pilot grant from Melanoma Research Alliance.