Two isoforms of otubain 1 regulate T cell anergy via GRAIL.
The active ubiquitin E3 ligase GRAIL is crucial in the induction of CD4 T cell anergy. Here we show that GRAIL is associated with and regulated by two isoforms of the ubiquitin-specific protease otubain 1. In lethally irradiated mice reconstituted with bone marrow cells from T cell receptor-transgenic mice retrovirally transduced to express the genes encoding these proteases, otubain 1-expressing cells contained negligible amounts of endogenous GRAIL, proliferated well and produced large amounts of interleukin 2 after antigenic stimulation. In contrast, cells expressing the alternatively spliced isoform, otubain 1 alternative reading frame 1, contained large amounts of endogenous GRAIL and were functionally anergic, and they proliferated poorly and produced undetectable interleukin 2 when stimulated in a similar way. Thus, these two proteins have opposing epistatic functions in controlling the stability of GRAIL expression and the resultant anergy phenotype in T cells.
Soares
Luis
L
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA.
Seroogy
Christine
C
Skrenta
Heidi
H
Anandasabapathy
Niroshana
N
Lovelace
Patricia
P
Chung
Chan D
CD
Engleman
Edgar
E
Fathman
C Garrison
CG
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D010450:Endopeptidases / Q000276:immunology*; D006801:Humans; D007527:Isoenzymes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*; D064570:Ubiquitin-Specific Proteases
D007527:Isoenzymes; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases