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

作者：Fukaya Makiko; Brorsson Caroline A; Meyerovich Kira; Catrysse Leen; Delaroche Diane; Vanzela Emerielle C; Ortis Fernanda; Beyaert Rudi; Nielsen Lotte B; Andersen Marie L; Mortensen Henrik B; Pociot Flemming; van Loo Geert; Storling Joachim; Cardozo Alessandra K^*

来源：Molecular Endocrinology, 2016, 30(1): 48-61.

DOI：10.1210/me.2015-1176

Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to beta-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-kappa B signaling and has strong antiapoptotic activities in beta-cells. Although the role of A20 on NF-kappa B 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 beta-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in beta-cells that are not restricted to inhibition of NF-kappa B. 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 beta-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of beta-cell survival and unveil novel mechanisms by which A20 controls beta-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.

• 出版日期2016-1