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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. / Berchtold, Lukas Adrian; Størling, Zenia Marian; Ortis, Fernanda; Lage, Kasper; Bang-Berthelsen, Claus; Bergholdt, Regine; Hald, Jacob; Brorsson, Caroline Anna; Eizirik, Decio Laks; Pociot, Flemming; Brunak, Søren; Størling, Joachim.

In: PNAS Early Edition, Vol. 108, No. 37, 2011, p. E681-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 2011, 'Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis', PNAS Early Edition, vol. 108, no. 37, pp. E681-8. https://doi.org/10.1073/pnas.1104384108

APA

Berchtold, L. A., Størling, Z. M., Ortis, F., Lage, K., Bang-Berthelsen, C., Bergholdt, R., Hald, J., Brorsson, C. A., Eizirik, D. L., Pociot, F., Brunak, S., & Størling, J. (2011). Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. PNAS Early Edition, 108(37), E681-8. https://doi.org/10.1073/pnas.1104384108

Vancouver

Berchtold LA, Størling ZM, Ortis F, Lage K, Bang-Berthelsen C, Bergholdt R et al. Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. PNAS Early Edition. 2011;108(37):E681-8. https://doi.org/10.1073/pnas.1104384108

Author

Berchtold, Lukas Adrian ; Størling, Zenia Marian ; Ortis, Fernanda ; Lage, Kasper ; Bang-Berthelsen, Claus ; Bergholdt, Regine ; Hald, Jacob ; Brorsson, Caroline Anna ; Eizirik, Decio Laks ; Pociot, Flemming ; Brunak, Søren ; Størling, Joachim. / Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis. In: PNAS Early Edition. 2011 ; Vol. 108, No. 37. pp. E681-8.

Bibtex

@article{d87544b6bd37449ab0f555bab133c37c,
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 {\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-1{\ss} 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-1{\ss}-induced NF-¿B activity and protection against IL-1{\ss}-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.",
keywords = "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",
author = "Berchtold, {Lukas Adrian} and St{\o}rling, {Zenia Marian} and Fernanda Ortis and Kasper Lage and Claus Bang-Berthelsen and Regine Bergholdt and Jacob Hald and Brorsson, {Caroline Anna} and Eizirik, {Decio Laks} and Flemming Pociot and S{\o}ren Brunak and Joachim St{\o}rling",
year = "2011",
doi = "10.1073/pnas.1104384108",
language = "English",
volume = "108",
pages = "E681--8",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "37",

}

RIS

TY - JOUR

T1 - Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis

AU - Berchtold, Lukas Adrian

AU - Størling, Zenia Marian

AU - Ortis, Fernanda

AU - Lage, Kasper

AU - Bang-Berthelsen, Claus

AU - Bergholdt, Regine

AU - Hald, Jacob

AU - Brorsson, Caroline Anna

AU - Eizirik, Decio Laks

AU - Pociot, Flemming

AU - Brunak, Søren

AU - Størling, Joachim

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Animals

KW - Apoptosis

KW - Binding Sites

KW - Cell Survival

KW - Child

KW - Cytokines

KW - Diabetes Mellitus, Type 1

KW - Female

KW - Genetic Predisposition to Disease

KW - Glucose

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Interleukin-1beta

KW - Male

KW - Mice

KW - Middle Aged

KW - NF-kappa B

KW - Nerve Tissue Proteins

KW - Polymorphism, Single Nucleotide

KW - Protein Binding

KW - Rats

KW - Transcription Factors

KW - Young Adult

U2 - 10.1073/pnas.1104384108

DO - 10.1073/pnas.1104384108

M3 - Journal article

C2 - 21705657

VL - 108

SP - E681-8

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 37

ER -

ID: 40804324