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; Narendra Wajapeyee

doi:10.1038/ncomms12639

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, Narendra Wajapeyee

Integrative Biology and Physiology

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English (US)
Article number	12639
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12639
State	Published - Aug 31 2016

Bibliographical note

Funding 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.

Publisher Copyright:
© 2016 The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1038/ncomms12639

Find It

Find It at U of M Libraries

Cite this

Nagarajan, A., Petersen, M. C., Nasiri, A. R., Butrico, G., Fung, A., Ruan, H. B., Kursawe, R., Caprio, S., Thibodeau, J., Bourgeois-Daigneault, M. C., Sun, L., Gao, G., Bhanot, S., Jurczak, M. J., Green, M. R., Shulman, G. I., & Wajapeyee, N. (2016). MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nature communications, 7, Article 12639. https://doi.org/10.1038/ncomms12639

Nagarajan, A, Petersen, MC, Nasiri, AR, Butrico, G, Fung, A, Ruan, HB, Kursawe, R, Caprio, S, Thibodeau, J, Bourgeois-Daigneault, MC, Sun, L, Gao, G, Bhanot, S, Jurczak, MJ, Green, MR, Shulman, GI & Wajapeyee, N 2016, 'MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels', Nature communications, vol. 7, 12639. https://doi.org/10.1038/ncomms12639

@article{9ab794083c3b4d35b639dd47d9a87e3a,

title = "MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels",

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.",

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

note = "Funding 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. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = aug,

day = "31",

doi = "10.1038/ncomms12639",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels

AU - Nagarajan, Arvindhan

AU - Petersen, Max C.

AU - Nasiri, Ali R.

AU - Butrico, Gina

AU - Fung, Annie

AU - Ruan, Hai Bin

AU - Kursawe, Romy

AU - Caprio, Sonia

AU - Thibodeau, Jacques

AU - Bourgeois-Daigneault, Marie Claude

AU - Sun, Lisha

AU - Gao, Guangping

AU - Bhanot, Sanjay

AU - Jurczak, Michael J.

AU - Green, Michael R.

AU - Shulman, Gerald I.

AU - Wajapeyee, Narendra

N1 - Funding 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. Publisher Copyright: © 2016 The Author(s).

PY - 2016/8/31

Y1 - 2016/8/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84985023406&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84985023406&partnerID=8YFLogxK

U2 - 10.1038/ncomms12639

DO - 10.1038/ncomms12639

M3 - Article

C2 - 27577745

AN - SCOPUS:84985023406

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 12639

ER -

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this