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Two isoforms of otubain 1 regulate T cell anergy via GRAIL

Nature Immunology volume 5, pages 45–54 (2004)Cite this article

Abstract

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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Figure 1: Expression pattern of otubain 1 in human tissues.
Figure 2: Otubain 1 and otubain 1 ARF-1 gene and protein.
Figure 3: Binding of otubain 1 and otubain 1 ARF-1 to GRAIL does not require an intact RING domain.
Figure 4: Stimulation-dependent degradation of GRAIL is enhanced by otubain 1 and inhibited by otubain 1 ARF-1.
Figure 5: Otubain 1 regulates GRAIL-mediated ubiquitination.
Figure 6: Otubain 1 has DUB activity towards isolated, branched polyubiquitin chains.
Figure 7: GRAIL, otubain 1 and USP8 form a trimolecular complex in cells.
Figure 8: Effects of otubain 1 or otubain 1 ARF-1 on T cell activation (anergy induction) and GRAIL expression in vivo.

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Acknowledgements

The authors thank J. Bogenberger for discussions; C. Holness and C. Taylor for technical assistance; and R. Kizer for assistance with manuscript preparation. Supported by the National Institute of Allergy and Infectious Diseases (AI-49903-02 to C.G.F. and AI01731-03 to C.M.S), and the National Cancer Institute (CA65237-14 to C.G.F., CA85774 to L.S. and E.E. and 5T32 AI07290-18 to C.D.C.).

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  1. Christine Seroogy

    Present address: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, 53792, USA

Authors and Affiliations

  1. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Luis Soares, Christine Seroogy, Heidi Skrenta, Niroshana Anandasabapathy, Chan D Chung & C Garrison Fathman

  2. Department of Pathology, Stanford University School of Medicine, 800 Welch Road, Palo Alto, 94304, California, USA

    Luis Soares, Patricia Lovelace & Edgar Engleman

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Correspondence to C Garrison Fathman.

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Soares, L., Seroogy, C., Skrenta, H. et al. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol 5, 45–54 (2004). https://doi.org/10.1038/ni1017

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