The transmembrane E3 ligase GRAIL ubiquitinates and degrades CD83 on CD4 T cells.
Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes, including T cell activation and tolerance. We have previously demonstrated that GRAIL (gene related to anergy in lymphocytes), a transmembrane RING finger ubiquitin E3 ligase, initially described as induced during the induction of CD4 T cell anergy, is also expressed in resting CD4 T cells. In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. Reduced CD83 surface expression levels were seen both on anergized CD4 T cells and following GRAIL expression by retroviral transduction, whereas GRAIL knock-down by RNA interference in CD4 T cells resulted in elevated CD83 levels. Furthermore, CD83 expression on CD4 T cells contributes to T cell activation as a costimulatory molecule. This study supports the novel mechanism of ubiquitination by GRAIL, identifies CD83 as a substrate of GRAIL, and ascribes a role for CD83 in CD4 T cell activation.
Su
Leon L
LL
Department of Medicine, Stanford University, CA 94040, USA.
Iwai
Hideyuki
H
Lin
Jack T
JT
Fathman
C Garrison
CG
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D017635:Clonal Anergy / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000378:metabolism; D054829:RING Finger Domains / Q000276:immunology; D013379:Substrate Specificity / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000097802:CD83 Antigen
D015703:Antigens, CD; D017874:Immediate-Early Proteins; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010447:Peptide Hydrolases; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C520250:RNF128 protein, human; C051804:Vmw110 protein, Human herpesvirus 1