Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster.
Agonist MHC-peptide complexes in the immunological synapse (IS) signal through T cell receptor (TCR) microclusters (MCs) that converge into a central supramolecular activation cluster (cSMAC). The determinants and function of the cSMAC remain unknown. We demonstrate an essential role for ubiquitin (Ub) and TSG101, but less so for HRS, in signal processing events at the cSMAC. Using siRNA in primary T cells, we show that Ub recognition by TSG101 is required for cSMAC formation, TCR MC signal termination, TCR downregulation, and segregation of TCR-MHC-peptide from PKC-theta-enriched signaling complexes. Weak agonist MHC-peptide induced CD80-dependent TCR MCs that dissociated in the center of the IS without recruiting TSG101. These results support TSG101-dependent recognition of CD80-independent TCR MCs as a molecular checkpoint for TCR downregulation.
Vardhana
Santosha
S
Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York, NY 10016, USA.
Choudhuri
Kaushik
K
Varma
Rajat
R
Dustin
Michael L
ML
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D000099177:Tsg101 Protein
D018122:B7-1 Antigen; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D025801:Ubiquitin; D000099177:Tsg101 Protein
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