Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins

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.

[1]  M. Daly,et al.  A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity. , 2014, American journal of human genetics.

[2]  P. Carroll,et al.  Adjustable Gastric Banding and Sleeve Gastrectomy in Bardet-Biedl Syndrome , 2014, Obesity Surgery.

[3]  E. Stone,et al.  CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype , 2014, Gene Therapy.

[4]  P. Jackson,et al.  Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. , 2013, Cell reports.

[5]  V. Sheffield,et al.  Subretinal gene therapy of mice with Bardet-Biedl syndrome type 1. , 2013, Investigative ophthalmology & visual science.

[6]  K. Uchiyama,et al.  Prions disturb post-Golgi trafficking of membrane proteins , 2013, Nature Communications.

[7]  N. Petrovsky,et al.  BBS-induced ciliary defect enhances adipogenesis, causing paradoxical higher-insulin sensitivity, glucose usage, and decreased inflammatory response. , 2012, Cell metabolism.

[8]  V. Sheffield,et al.  Intrinsic Protein-Protein Interaction-mediated and Chaperonin-assisted Sequential Assembly of Stable Bardet-Biedl Syndrome Protein Complex, the BBSome* , 2012, The Journal of Biological Chemistry.

[9]  V. Sheffield,et al.  BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes , 2012, Human molecular genetics.

[10]  V. Sheffield,et al.  Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes , 2011, Proceedings of the National Academy of Sciences.

[11]  V. Sheffield,et al.  A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened , 2011, PLoS genetics.

[12]  Andrew D. Johnson,et al.  Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet-Biedl syndrome proteins , 2011, Cellular and Molecular Life Sciences.

[13]  H. Dollfus,et al.  Bardet-Biedl syndrome highlights the major role of the primary cilium in efficient water reabsorption. , 2011, Kidney international.

[14]  V. Sheffield,et al.  Inactivation of Bardet-Biedl syndrome genes causes kidney defects. , 2011, American journal of physiology. Renal physiology.

[15]  L. Biesecker,et al.  Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance. , 2011, The Journal of clinical endocrinology and metabolism.

[16]  D. Morgan,et al.  Differential effects of insulin on sympathetic nerve activity in agouti obese mice , 2010, Journal of hypertension.

[17]  G. Elia.  Protein Biotinylation , 2010, Current protocols in protein science.

[18]  V. Sheffield,et al.  BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly , 2010, Proceedings of the National Academy of Sciences.

[19]  Nicholas Katsanis,et al.  Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. , 2009, The Journal of clinical investigation.

[20]  V. Sheffield,et al.  Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling , 2009, Human molecular genetics.

[21]  G. Bishop,et al.  Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia , 2008, Proceedings of the National Academy of Sciences.

[22]  V. Sheffield,et al.  A knockin mouse model of the Bardet–Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity , 2007, Proceedings of the National Academy of Sciences.

[23]  D. Catalucci,et al.  Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action , 2007, PloS one.

[24]  V. Sheffield,et al.  A Core Complex of BBS Proteins Cooperates with the GTPase Rab8 to Promote Ciliary Membrane Biogenesis , 2007, Cell.

[25]  Nicholas Katsanis,et al.  The ciliopathies: an emerging class of human genetic disorders. , 2006, Annual review of genomics and human genetics.

[26]  O. Blacque,et al.  Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport , 2006, Cellular and Molecular Life Sciences CMLS.

[27]  M. Walker,et al.  Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. , 2006, The Journal of clinical endocrinology and metabolism.

[28]  J. Lupski,et al.  Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity , 2006, Human Genetics.

[29]  V. Sheffield,et al.  Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. , 2006, Human molecular genetics.

[30]  B. Fernandez,et al.  Clinical and genetic epidemiology of Bardet–Biedl syndrome in Newfoundland: A 22‐year prospective, population‐based, cohort study , 2005, American journal of medical genetics. Part A.

[31]  C. Summerbell,et al.  Energy metabolism in Bardet–Biedl syndrome , 2003, International Journal of Obesity.

[32]  Val C. Sheffield,et al.  Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome , 2002, Nature Genetics.

[33]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[34]  R. Leduc,et al.  Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity. , 2000, Biochimica et biophysica acta.

[35]  P. Parfrey,et al.  The importance of renal impairment in the natural history of Bardet-Biedl syndrome. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[36]  A. Williams,et al.  Hyperproinsulinaemia in patients with myotonic dystrophy , 1992, Diabetologia.

[37]  V. P. Knutson,et al.  Cellular trafficking and processing of the insulin receptor 1 , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  W. Pryse-Phillips,et al.  The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. , 1989, The New England journal of medicine.

[39]  J. Carpentier,et al.  Biosynthesis and regulation of the insulin receptor. , 1989, The Yale journal of biology and medicine.

[40]  G. Ronnett,et al.  Role of glycosylation in the processing of newly translated insulin proreceptor in 3T3-L1 adipocytes. , 1984, Journal of Biological Chemistry.

[41]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[42]  H. Dollfus,et al.  Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[43]  H. Till,et al.  Roux-en-Y Gastric Bypass in an Adolescent Patient with Bardet–Biedl Syndrome, a Monogenic Obesity Disorder , 2010, Obesity surgery.

[44]  F. Plewniak,et al.  Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. , 2007, American journal of human genetics.

[45]  J. Bickenbach.  Isolation, characterization, and culture of epithelial stem cells. , 2005, Methods in molecular biology.