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

Lukas Adrian Berchtold; Zenia Marian Størling; Fernanda Ortis; Kasper Lage; Claus Bang-Berthelsen; Regine Bergholdt; Jacob Hald; Caroline Anna Brorsson; Decio Laks Eizirik; Flemming Pociot; Søren Brunak; Joachim Størling

doi:10.1073/pnas.1104384108

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

Lukas Adrian Berchtold, Zenia Marian Størling, Fernanda Ortis, Kasper Lage, Claus Bang-Berthelsen, Regine Bergholdt, Jacob Hald, Caroline Anna Brorsson, Decio Laks Eizirik, Flemming Pociot, Søren Brunak, Joachim Størling

49 Citations (Scopus)

Abstract

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 topscoring candidate gene was huntingtin-interacting protein (HIP)- 14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulinpositive 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.

Original language	English
Journal	PNAS Early Edition
Volume	108
Issue number	37
Pages (from-to)	E681-8
DOIs	https://doi.org/10.1073/pnas.1104384108
Publication status	Published - 13 Sept 2011

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1104384108

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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

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

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abstract = "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 topscoring candidate gene was huntingtin-interacting protein (HIP)- 14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulinpositive 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.",

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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 - 2011/9/13

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N2 - 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 topscoring candidate gene was huntingtin-interacting protein (HIP)- 14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulinpositive 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.

AB - 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 topscoring candidate gene was huntingtin-interacting protein (HIP)- 14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulinpositive 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.

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

SN - 0027-8424

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

IS - 37

ER -

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

Abstract

Keywords

UN SDGs

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