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Two isoforms of otubain 1 regulate T cell anergy via GRAIL.

Nature immunology | Jan 30, 2004

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.

Pubmed ID: 14661020 RIS Download

Mesh terms: Alternative Splicing | Amino Acid Sequence | Animals | Base Sequence | CD4-Positive T-Lymphocytes | Cell Division | Clonal Anergy | Endopeptidases | Humans | Isoenzymes | Mice | Mice, Inbred BALB C | Mice, Transgenic | Molecular Sequence Data | Sequence Alignment | Two-Hybrid System Techniques | Ubiquitin | Ubiquitin-Protein Ligases | Ubiquitin-Specific Proteases

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Associated grants

  • Agency: NIAID NIH HHS, Id: 5T32 AI07290-18
  • Agency: NIAID NIH HHS, Id: AI-49903-02
  • Agency: NIAID NIH HHS, Id: AI01731-03
  • Agency: NCI NIH HHS, Id: CA65237-14
  • Agency: NCI NIH HHS, Id: CA85774

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