SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation.
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.
Choi
Young Bong
YB
Department of Life Science, Ewha Woman's University, 120-750 Seoul, Korea.
Son
Myoungsun
M
Park
Mijin
M
Shin
Jaekyoon
J
Yun
Yungdae
Y
D000818:Animals; D001665:Binding Sites; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D020798:Two-Hybrid System Techniques
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; C473085:SOCS6 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D046988:Proteasome Endopeptidase Complex