SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation

J Biol Chem. 2010 Mar 5;285(10):7271-80. doi: 10.1074/jbc.M109.073726. Epub 2009 Dec 10.

Abstract

The T cell-specific tyrosine kinase, p56(lck), plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56(lck). SOCS-6 was identified as a protein binding to the kinase domain of p56(lck) through yeast two-hybrid screening. SOCS-6 bound specifically to p56(lck) (F505), which mimics the active form of p56(lck), but not to wild type p56(lck). In Jurkat T cells, SOCS-6 binding to p56(lck) was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56(lck). SOCS-6 promoted p56(lck) ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Humans
  • Immunological Synapses / metabolism
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Lymphocyte Activation*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Mice
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / physiology*
  • Two-Hybrid System Techniques

Substances

  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • SOCS6 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proteasome Endopeptidase Complex