GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells.
T cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4(+) T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype.
Anandasabapathy
Niroshana
N
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CA 94305, USA.
Ford
Gregory S
GS
Bloom
Debra
D
Holness
Claire
C
Paragas
Violette
V
Seroogy
Christine
C
Skrenta
Heidi
H
Hollenhorst
Marie
M
Fathman
C Garrison
CG
Soares
Luis
L
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019703:Calcineurin / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics*; D004705:Endocytosis; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008025:Ligases / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D014158:Transcription, Genetic; D014168:Transferrin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015032:Zinc / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D014168:Transferrin; D015759:Ionomycin; D044767:Ubiquitin-Protein Ligases; D019703:Calcineurin; D008025:Ligases; D015032:Zinc