ArticleThe EMBO journal2010
Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development.
Article in The EMBO journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 49 citations in OpenAlex.
- LAG3 checkpoint function and its mechanism of action in therapeutic targeting.Nature reviews. Immunology · 2026Review
- A proximity ligation screen identifies SNAT2 as a novel target of the MARCH1 E3 ubiquitin ligase.Biology open · 2026Article
- A distinct TCRiScience · 2026Article
- Targeting organelle function in T cells for cancer immunotherapy.Nature reviews. Immunology · 2026Review
- Decoding LAG3 activation: ubiquitination liberates immunosuppressive motif to license checkpoint function.Molecular biomedicine · 2025Article
- The LDH-H3K18La-Nur77 Axis Potentiates Immune Escape in Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Tailoring CAR surface density and dynamics to improve CAR-T cell therapy.Journal for immunotherapy of cancer · 2025Review
- The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression.International journal of molecular sciences · 2023Article
- CD3e-immunotoxin spares CD62LFrontiers in immunology · 2022Article
- Separate signaling events control TCR downregulation and T cell activation in primary human T cells.Immunity, inflammation and disease · 2021Article
- Genetically modified hematopoietic stem/progenitor cells that produce IL-10-secreting regulatory T cells.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dual TCR T Cells: Identity Crisis or Multitaskers?Journal of immunology (Baltimore, Md. : 1950) · 2019Review
- Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation.Molecular systems biology · 2016Article
- Usp12 stabilizes the T-cell receptor complex at the cell surface during signaling.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T-cell costimulatory receptor.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Silencing autocrine death: a ubiquitin ligase that blocks activation-induced cell death in cutaneous T-cell lymphoma.The Journal of investigative dermatology · 2015Article
- The Emerging and Diverse Roles of Src-Like Adaptor Proteins in Health and Disease.Mediators of inflammation · 2015Review
- Mammalian target of rapamycin complex 2 modulates αβTCR processing and surface expression during thymocyte development.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
- Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
Corrections and comments
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Authors and funding
14 authors at 7 institutions in 2 countries.
Funding
Abstract
Expression of the T-cell receptor (TCR):CD3 complex is tightly regulated during T-cell development. The mechanism and physiological role of this regulation are unclear. Here, we show that the TCR:CD3 complex is constitutively ubiquitylated in immature double positive (DP) thymocytes, but not mature single positive (SP) thymocytes or splenic T cells. This steady state, tonic CD3 monoubiquitylation is mediated by the CD3varepsilon proline-rich sequence, Lck, c-Cbl, and SLAP, which collectively trigger the dynamin-dependent downmodulation, lysosomal sequestration and degradation of surface TCR:CD3 complexes. Blocking this tonic ubiquitylation by mutating all the lysines in the CD3 cytoplasmic tails significantly upregulates TCR levels on DP thymocytes. Mimicking monoubiquitylation by expression of a CD3zeta-monoubiquitin (monoUb) fusion molecule significantly reduces TCR levels on immature thymocytes. Moreover, modulating CD3 ubiquitylation alters immunological synapse (IS) formation and Erk phosphorylation, thereby shifting the signalling threshold for positive and negative selection, and regulatory T-cell development. Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T-cell development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.