In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 37 ( 2011-09-13)
Abstract:
In summary, we have identified HIP14 as a T1D protein with important biological functions, such as the control of insulin secretion and apoptosis, in pancreatic β-cells. The prediction and functional β-cell validation of HIP14 underlines the current network biology approach as a valid method to identify genes of importance for T1D. These findings may therefore embody the basis for unique therapeutic approaches aimed at increasing the β-cell expression of HIP14 as a means to circumvent β-cell failure in T1D. We recently developed a bioinformatics network biology method, known as the “phenome–interactome network analysis,” for the in silico prediction of proteins and genes involved in disease phenotypes ( 1 ). This method prioritizes candidates on the basis of their physical interactions at the protein level with other proteins involved in the specific disease phenotype ( Fig. P1 ). In the present study, we applied this method to identify candidate proteins that play putative roles in the pathogenesis of T1D. Specifically, we examined a previously published dataset that revealed 11 genomic regions with linkage to T1D ( 2 ). All genes located within 10 Mb of the markers were extracted and used for the phenome–interactome network analysis (i.e., for all of the extracted genes, protein networks were generated according to high-confidence protein–protein interaction data) ( Fig. P1 ) ( 1 ). In total, the method predicted 11 T1D candidates, including insulin ( INS ), which is a well known T1D-associated gene. A top-scoring T1D candidate was huntingtin-interacting protein (HIP)-14 (also known as ZDHHC17). Previous reports have established HIP14 as a protein most highly expressed in the brain, where it plays normal physiological roles in protein trafficking and vesicle exocytosis ( 3 – 5 ). However, in relation to diabetes, the function of HIP14 is hitherto completely unknown. We therefore examined the biological and functional roles of HIP14 in pancreatic β-cells, the target tissue in T1D, and the main findings are listed in Fig. P1 . We demonstrate that HIP14 is expressed in both β-cell lines and rodent and human islets. Immunohistochemical staining of mouse pancreatic sections and comparison of HIP14 expression in α- vs. β-cells showed that in the islets of Langerhans, HIP14 is preferentially expressed in insulin-positive cells, indicating that HIP14 may play an im-portant functional role in β-cells as opposed to other islet cell types. Indeed, RNAi knockdown experiments demonstrated that HIP14 is required for β-cell survival and growth of insulin-secreting rat INS-1 cells and purified primary rat β-cells. In addition, HIP14 was also found to be required for glucose-stimulated insulin secretion. We also found that HIP14 is a target of proinflammatory cytokines (IL-1β and IFN-γ) known to contribute to β-cell dysfunction in T1D. Hence, exposure of INS-1 cells or rat islets to cytokines caused a decrease in HIP14 protein expression. Further, cytokines decreased HIP14 mRNA expression in six of eight human islet preparations. These findings suggest that cytokines impair β-cell function, likely owing to the down-regulation of HIP14, ultimately resulting in decreased insulin secretion and apoptosis. Consistently, overexpression of HIP14 caused a reduction in IL-1β–induced NF-κB activity and diminished IL-1β–induced apoptotic cell death. Finally, we performed bioinformatics analyses and identified SNPs associated with T1D in transcription factor binding sites located upstream of the HIP14 gene, thereby potentially affecting HIP14 expression in T1D, and thus providing a possible link between genetic variation in the HIP14 locus and impaired β-cell function. Type 1 diabetes (T1D) is a complex autoimmune disease in which the insulin-producing pancreatic β-cells are destroyed. Although the disease has a strong genetic component and several loci are known to increase susceptibility to T1D, only relatively few causal genes have currently been identified.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1104384108
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2011
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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