Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination

J Exp Med. 2016 Mar 7;213(3):399-414. doi: 10.1084/jem.20151426. Epub 2016 Feb 22.

Abstract

Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology
  • Amino Acid Sequence
  • Animals
  • Autoimmunity
  • Cell Differentiation
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Endopeptidases / deficiency
  • Endopeptidases / metabolism*
  • Epitopes / immunology
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Inflammation / immunology*
  • Inflammation / pathology
  • Lymphocyte Activation / immunology*
  • Lymphopenia / immunology
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Ubiquitination*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*

Substances

  • Epitopes
  • Peptides
  • Receptors, Antigen, T-Cell
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • Endopeptidases
  • Otud7b protein, mouse
  • Lysine