Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis
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Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting ß-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 ß-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1ß and IFN-¿) that mediate ß-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-1ß-induced NF-¿B activity and protection against IL-1ß-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.
|PNAS Early Edition
|Published - 2011
- 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, Interleukin-1beta, Male, Mice, Middle Aged, NF-kappa B, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein Binding, Rats, Transcription Factors, Young Adult