Nature communications, 2024-01, Vol.15 (1), p.532-532, Article 532
2024
Details
- Autor(en) / Beteiligte
- Titel
- The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
- Ist Teil von
- Nature communications, 2024-01, Vol.15 (1), p.532-532, Article 532
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive upstream regulator of Lck during T-cell activation. DUSP22 dephosphorylates UBR2 at specific Serine residues, leading to ubiquitin-mediated UBR2 degradation. UBR2 is also modified by the SCF E3 ubiquitin ligase complex via Lys48-linked ubiquitination at multiple Lysine residues. Single-cell RNA sequencing analysis and UBR2 loss of function experiments showed that UBR2 is a positive regulator of proinflammatory cytokine expression. Mechanistically, UBR2 induces Lys63-linked ubiquitination of Lck at Lys99 and Lys276 residues, followed by Lck Tyr394 phosphorylation and activation as part of TCR signalling. Inflammatory phenotypes induced by TCR-triggered Lck activation or knocking out DUSP22, are attenuated by genomic deletion of UBR2. UBR2-Lck interaction and Lck Lys63-linked ubiquitination are induced in the peripheral blood T cells of human SLE patients, which demonstrate the relevance of the UBR2-mediated regulation of inflammation to human pathology. In summary, we show here an important regulatory mechanism of T cell activation, which finetunes the balance between T cell response and aggravated inflammation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-024-44843-wTitel-ID: cdi_doaj_primary_oai_doaj_org_article_74ada20324de4b6ca3ec165d10c91490
- Format
- –
- Schlagworte
- Cell activation, Dual-Specificity Phosphatases - genetics, Dual-Specificity Phosphatases - metabolism, Gene sequencing, Human pathology, Humans, Inflammation, Inflammation - genetics, Kinases, Lck protein, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism, Lymphocytes, Lymphocytes T, Lysine, Mitogen-Activated Protein Kinase Phosphatases - genetics, Mitogen-Activated Protein Kinase Phosphatases - metabolism, Peripheral blood, Phenotypes, Phosphatase, Phosphorylation, Receptors, Antigen, T-Cell - metabolism, Regulatory mechanisms (biology), Regulatory sequences, Residues, Sequence analysis, T cell receptors, Ubiquitin-protein ligase, Ubiquitin-Protein Ligases - genetics, Ubiquitin-Protein Ligases - metabolism, Ubiquitination