title: Preventing p38 MAPK-mediated MafA degradation ameliorates β-cell dysfunction under oxidative stress.
abstract: The reduction in the expression of glucose-responsive insulin gene transcription factor MafA accompanies the development of β-cell dysfunction under oxidative stress/diabetic milieu. Humans with type 2 diabetes have reduced MafA expression, and thus preventing this reduction could overcome β-cell dysfunction and diabetes. We previously showed that p38 MAPK, but not glycogen synthase kinase 3 (GSK3), is a major regulator of MafA degradation under oxidative stress. Here, we examined the mechanisms of this degradation and whether preventing MafA degradation under oxidative stress will overcome β-cell dysfunction. We show that under oxidative and nonoxidative conditions p38 MAPK directly binds to MafA and triggers MafA degradation via ubiquitin proteasomal pathway. However, unlike nonoxidative conditions, MafA degradation under oxidative stress depended on p38 MAPK-mediated phosphorylation at threonine (T) 134, and not T57. Furthermore the expression of alanine (A) 134-MafA, but not A57-MafA, reduced the oxidative stress-mediated loss of glucose-stimulated insulin secretion, which was independent of p38 MAPK action on protein kinase D, a regulator of insulin secretion. Interestingly, the expression of proteasomal activator PA28γ that degrades GSK3-phosphorylated (including T57) MafA was reduced under oxidative stress, explaining the dominance of p38 MAPK over the GSK3 pathway in regulating MafA stability under oxidative stress. These results identify two distinct pathways mediating p38 MAPK-dependent MafA degradation under oxidative and nonoxidative conditions and show that inhibiting MafA degradation under oxidative stress ameliorates β-cell dysfunction and could lead to novel therapies for diabetes.
authors: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors: Ilham
authors: I
authors: El Khattabi
authors: Arun
authors: A
authors: Sharma
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D051473:Maf Transcription Factors, Large / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D007328:Insulin; C099558:Ki antigen; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D025801:Ubiquitin; D010769:Phosphothreonine; C089212:protein kinase D; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex
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