Journal
NATURE IMMUNOLOGY
Volume 5, Issue 1, Pages 45-54Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni1017
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Funding
- NCI NIH HHS [CA85774, CA65237-14] Funding Source: Medline
- NIAID NIH HHS [5T32 AI07290-18, AI-49903-02, AI01731-03] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA065237, R01CA085774] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI049903, T32AI007290] Funding Source: NIH RePORTER
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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.
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