The Transmembrane E3 Ligase GRAIL Ubiquitinates and Degrades CD83 on CD4 T Cells

• Published in: The Journal of immunology (1950) 2009-07, Vol.183 (1), p.438-444
• Main Authors: Su, Leon L, Iwai, Hideyuki, Lin, Jack T, Fathman, C. Garrison
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigens, CD - biosynthesis; Antigens, CD - genetics; Antigens, CD - metabolism; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD83 Antigen; Cell Line; Clonal Anergy - immunology; Down-Regulation - immunology; Herpesvirus 1, Human - immunology; Humans; Immediate-Early Proteins - physiology; Immunoglobulins - biosynthesis; Immunoglobulins - genetics; Immunoglobulins - metabolism; Lymphocyte Activation - immunology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Molecular Sequence Data; Peptide Hydrolases - metabolism; RING Finger Domains - immunology; Substrate Specificity - immunology; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900204

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.