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PLoS Genet. 2015 Jun 23;11(6):e1005311. doi: 10.1371/journal.pgen.1005311. eCollection 2015 Jun.

Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins.

Author information

1
Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa, United States of America.
2
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, United States of America.
3
Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa, United States of America; Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa, United States of America.
4
Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa, United States of America; Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, United States of America; FOE Diabetes Research Center, University of Iowa College of Medicine, Iowa City, Iowa, United States of America.

Abstract

Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene.

PMID:
26103456
PMCID:
PMC4478011
DOI:
10.1371/journal.pgen.1005311
[Indexed for MEDLINE]
Free PMC Article

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