• Luis Soares, Christine Seroogy, Heidi Skrenta, Niroshana Anandasabapathy, Patricia Lovelace, Chan D Chung, Edgar Engleman, and C Garrison Fathman.
• Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA.
• Nat. Immunol. 2004 Jan 1; 5 (1): 45-54.

AbstractThe 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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