title: Cutting edge: The transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy.
abstract: Activation of naive T lymphocytes is regulated through a series of discrete checkpoints that maintain unresponsiveness to self. During this multistep process, costimulatory interactions act as inducible signals that allow APCs to selectively mobilize T cells against foreign Ags. In this study, we provide evidence that the anergy-associated E3 ubiquitin ligase GRAIL (gene related to anergy in lymphocytes) regulates expression of the costimulatory molecule CD40L on CD4 T cells. Using its luminal protease-associated domain, GRAIL binds to the luminal/extracellular portion of CD40L and facilitates transfer of ubiquitin molecules from the intracellular GRAIL RING (really interesting new gene) finger to the small cytosolic portion of CD40L. Down-regulation of CD40L occurred following ectopic expression of GRAIL in naive T cells from CD40(-/-) mice, and expression of GRAIL in bone marrow chimeric mice was associated with diminished lymphoid follicle formation. These data provide a model for intrinsic T cell regulation of costimulatory molecules and a molecular framework for the initiation of clonal T cell anergy.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Lineberry
authors.forename: Leon L
authors.initials: LL
authors.lastname: Su
authors.forename: Jack T
authors.initials: JT
authors.lastname: Lin
authors.forename: Greg P
authors.initials: GP
authors.lastname: Coffey
authors.forename: Christine M
authors.initials: CM
authors.lastname: Seroogy
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000276:immunology* / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D023201:CD40 Ligand; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases