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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.

Pubmed ID: 14661020

Authors

  • Soares L
  • Seroogy C
  • Skrenta H
  • Anandasabapathy N
  • Lovelace P
  • Chung CD
  • Engleman E
  • Fathman CG

Journal

Nature immunology

Publication Data

January 30, 2004

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

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