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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Lukas Adrian Berchtold
  • Zenia Marian Størling
  • Fernanda Ortis
  • Kasper Lage
  • Claus Bang-Berthelsen
  • Regine Bergholdt
  • Jacob Hald
  • Caroline Anna Brorsson
  • Decio Laks Eizirik
  • Pociot, Flemming
  • Brunak, Søren
  • Joachim Størling
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.
Original languageEnglish
JournalPNAS Early Edition
Volume108
Issue number37
Pages (from-to)E681-8
DOIs
Publication statusPublished - 2011

    Research areas

  • 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

ID: 40804324