A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes

Mol Endocrinol. 2016 Jan;30(1):48-61. doi: 10.1210/me.2015-1176. Epub 2015 Dec 10.

Abstract

Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to β-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-κB signaling and has strong antiapoptotic activities in β-cells. Although the role of A20 on NF-κB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the β-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in β-cells that are not restricted to inhibition of NF-κB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual β-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of β-cell survival and unveil novel mechanisms by which A20 controls β-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Child
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Polymorphism, Single Nucleotide
  • Rats
  • Signal Transduction / physiology
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse

Grant support

Work in A.K.C. group was supported by the Juvenile Diabetes Foundation, New York, Grant 1–2011-589; Actions de Recherche Concertées de la Communauté Française (Belgium); and National Funds from Scientific Research (FNRS) (Belgium, MIS Grant F.4521.11). Work in the G.v.L. and R.B. labs was supported by an Research Foundation Flanders (FWO) Odysseus Grant and by research grants from the FWO (Belgium), the Innovatie door Wetenschap en Technologie (IWT) strategic basic research program, the Belgian Foundation Against Cancer, the Geneeskundige Stichting Koningin Elisabeth (Belgium), the Charcot Foundation (Belgium), the Interuniversity Attraction Poles program (IAP7, Belgium), and the Concerted Research Actions (Belgium) and Group-ID Multidisciplinary Research Partnership (MRP) of the Gent University. Work in the J.S. lab was funded by the Danish Research Council (Denmark) Grant 1331–00163A. The research of F.O. was supported by Fundação de Auxilio a Pesquisa do Estado de São Paulo (Brazil). E.C.V. received a Postdoctoral Fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/Wallonie-Bruxelles International (WBI), Belgium/Brazil).