Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis.

Berchtold LA, Størling ZM, Ortis F, Lage K, Bang-Berthelsen C, Bergholdt R, Hald J, Brorsson CA, Eizirik DL, Pociot F, Brunak S, Størling J
Proc Natl Acad Sci U S A. 2011 108 (37): E681-8

PMID: 21705657 · PMCID: PMC3174627 · DOI:10.1073/pnas.1104384108

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.

MeSH Terms (27)

Adolescent Adult Animals Apoptosis Binding Sites Cell Survival Child Cytokines Diabetes Mellitus, Type 1 Female Genetic Predisposition to Disease Glucose Humans Insulin Insulin-Secreting Cells Insulin Secretion Interleukin-1beta Male Mice Middle Aged Nerve Tissue Proteins NF-kappa B Polymorphism, Single Nucleotide Protein Binding Rats Transcription Factors Young Adult

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