title: Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis.
abstract: Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting β-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico "phenome-interactome analysis" on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for β-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1β and IFN-γ) that mediate β-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1β-induced NF-κB activity and protection against IL-1β-mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches.
authors.affiliation: Hagedorn Research Institute, 2820 Gentofte, Denmark.
authors.forename: Lukas Adrian
authors.initials: LA
authors.lastname: Berchtold
authors.forename: Zenia Marian
authors.initials: ZM
authors.lastname: Størling
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ortis
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.forename: Claus
authors.initials: C
authors.lastname: Bang-Berthelsen
authors.forename: Regine
authors.initials: R
authors.lastname: Bergholdt
authors.forename: Jacob
authors.initials: J
authors.lastname: Hald
authors.forename: Caroline Anna
authors.initials: CA
authors.lastname: Brorsson
authors.forename: Decio Laks
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D007328:Insulin; D053583:Interleukin-1beta; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D005947:Glucose