Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation.
The dynamic modification of nuclear and cytoplasmic proteins with O-linked beta-N-acetylglucosamine (O-GlcNAc) by the O-linked N-acetylglucosaminyltransferase (OGT) is a regulatory post-translational modification that is responsive to various stimuli. Here, we demonstrate that OGT is a central factor for T- and B-lymphocytes activation. SiRNA-mediated knockdown of OGT in T cells leads to an impaired activation of the transcription factors NFAT and NFkappaB. This results in a reduction of IL-2 production consistent with prevention of T-cell activation. OGT is also required for the early activation of B cells mediated by stimulation of the B-cell receptor. Mechanistically, we demonstrate that NFkappaB as well as NFAT are glycosylated with O-GlcNAc after direct binding to OGT. Moreover, kinetic experiments show that O-GlcNAc modification prominently increased shortly after activation of lymphoid cells and it might be required for nuclear translocation of the transcription factors NFkappaB and NFAT.
Golks
Alexander
A
Autoimmunity and Transplantation, Novartis Pharma AG, Basel, Switzerland.
Tran
Thi-Thanh Thao
TT
Goetschy
Jean Francois
JF
Guerini
Danilo
D
D017398:Alternative Splicing; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism*; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D037181:Lectins, C-Type; D017351:N-Acetylglucosaminyltransferases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D000099192:CD69 Antigens; C494006:NFATC2 protein, human; C037649:N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase