Your browser doesn't support javascript.
loading
Negative regulation of FOXP3 expression by c-Rel O-GlcNAcylation.
de Jesus, Tristan J; Tomalka, Jeffrey A; Centore, Joshua T; Staback Rodriguez, Franklin D; Agarwal, Ruchira A; Liu, Angela R; Kern, Timothy S; Ramakrishnan, Parameswaran.
Afiliación
  • de Jesus TJ; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Tomalka JA; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Centore JT; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Staback Rodriguez FD; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Agarwal RA; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Liu AR; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
  • Kern TS; Department of Ophthalmology, School of Medicine, University of California Irvine, 850 Health Sciences Road Irvine, CA 92697, USA.
  • Ramakrishnan P; Department of Pathology, School of Medicine, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA.
Glycobiology ; 31(7): 812-826, 2021 08 07.
Article en En | MEDLINE | ID: mdl-33442719
O-GlcNAcylation is a reversible post-translational protein modification that regulates fundamental cellular processes including immune responses and autoimmunity. Previously, we showed that hyperglycemia increases O-GlcNAcylation of the transcription factor, nuclear factor kappaB c-Rel at serine residue 350 and enhances the transcription of the c-Rel-dependent proautoimmune cytokines interleukin-2, interferon gamma and granulocyte macrophage colony stimulating factor in T cells. c-Rel also plays a critical role in the transcriptional regulation of forkhead box P3 (FOXP3)-the master transcription factor that governs development and function of Treg cells. Here we show that the regulatory effect of c-Rel O-GlcNAcylation is gene-dependent, and in contrast to its role in enhancing the expression of proautoimmune cytokines, it suppresses the expression of FOXP3. Hyperglycemia-induced O-GlcNAcylation-dependent suppression of FOXP3 expression was found in vivo in two mouse models of autoimmune diabetes; streptozotocin-induced diabetes and spontaneous diabetes in nonobese diabetic mice. Mechanistically, we show that both hyperglycemia-induced and chemically enhanced cellular O-GlcNAcylation decreases c-Rel binding at the FOXP3 promoter and negatively regulates FOXP3 expression. Mutation of the O-GlcNAcylation site in c-Rel, (serine 350 to alanine), augments T cell receptor-induced FOXP3 expression and resists the O-GlcNAcylation-dependent repression of FOXP3 expression. This study reveals c-Rel S350 O-GlcNAcylation as a novel molecular mechanism inversely regulating immunosuppressive FOXP3 expression and proautoimmune gene expression in autoimmune diabetes with potential therapeutic implications.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-rel / Diabetes Mellitus Experimental / Factores de Transcripción Forkhead Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Glycobiology Asunto de la revista: BIOQUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-rel / Diabetes Mellitus Experimental / Factores de Transcripción Forkhead Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Glycobiology Asunto de la revista: BIOQUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido