title: A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes.
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.
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Makiko
authors.initials: M
authors.lastname: Fukaya
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Brorsson
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Kira
authors.initials: K
authors.lastname: Meyerovich
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Leen
authors.initials: L
authors.lastname: Catrysse
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Diane
authors.initials: D
authors.lastname: Delaroche
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Emerielle C
authors.initials: EC
authors.lastname: Vanzela
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ortis
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Nielsen
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Andersen
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Mortensen
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.affiliation: Université Libre de Bruxelles Center for Diabetes Research (M.F., K.M., D.D., E.C.V., A.K.C.), Free University Brussels, 1070 Brussels, Belgium; Copenhagen Diabetes Research Center (C.A.B., L.B.N., M.L.A., H.B.M., F.P., J.S.), Department of Pediatrics E, Copenhagen University Hospital Herlev, DL-2730 Herlev, Denmark; Inflammation Research Center (L.C., R.B., G.v.L.), Vlaams Instituut voor Biotechnologie, 9052 Gent, Belgium; Department of Biomedical Molecular Biology (L.C., R.B., G.v.L.), 9052 Gent University, Gent, Belgium; Laboratory of Endocrine Pancreas and Metabolism (E.C.V.), Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-970 Campinas, Brazil; and Department of Development and Cellular Biology (F.O.), Institute of Biomedical Sciences, 05508-900 São Paulo University, São Paulo, Brazil.
authors.forename: Alessandra K
authors.initials: AK
authors.lastname: Cardozo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002648:Child; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse