SUMO conjugation contributes to immune deviation in nonobese diabetic mice by suppressing c-Maf transactivation of IL-4.
It is not clear why the development of protective Th2 cells is poor in type 1 diabetes (T1D). c-Maf transactivates the IL-4 gene promoting Th2 cell development; therefore, abnormalities in c-Maf may contribute to reduced IL-4 production by CD4 cells from nonobese diabetic (NOD) mice. In this study we demonstrate that despite normal expression, c-Maf binds poorly to the IL-4 promoter (IL-4p) in NOD CD4 cells. Immunoblotting demonstrates that c-Maf can be modified at lysine 33 by SUMO-1 (small ubiquitin-like modifier 1). Sumoylation is facilitated by direct interaction with the E2-conjugating enzyme Ubc9 and increases following T cell stimulation. In transfected cells, sumoylation decreases c-Maf transactivation of IL-4p-driven luciferase reporter activity, reduces c-Maf binding to the IL-4p in chromatin immunoprecipitation assays, and enhances c-Maf localization into promyelocytic leukemia nuclear bodies. Sumoylation of c-Maf is increased in NOD CD4 cells as compared with CD4 cells from diabetes-resistant B10.D2 mice, suggesting that increased c-Maf sumoylation contributes to immune deviation in T1D by reducing c-Maf access to and transactivation of the IL-4 gene.
Leavenworth
Jianmei W
JW
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA.
Ma
Xiaojing
X
Mo
Yin-yuan
YY
Pauza
Mary E
ME
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D007109:Immunity; D015847:Interleukin-4 / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism / Q000502:physiology*; D025842:SUMO-1 Protein / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*
C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D025842:SUMO-1 Protein; D015847:Interleukin-4; D008239:Lysine