The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling

• Published in: Nature communications 2024-01, Vol.15 (1), p.532-532, Article 532
• Main Authors: Shih, Ying-Chun, Chen, Hsueh-Fen, Wu, Chia-Ying, Ciou, Yi-Ru, Wang, Chia-Wen, Chuang, Huai-Chia, Tan, Tse-Hua
• Format: Article
• Language: English
• Subjects: 14/19; 631/250/1619/554/1775; 631/250/516; 631/45/474/2073; 631/80/458/1733; 64/60; 82/51; 82/58; 96/31; 96/95; Cell activation; Dual-Specificity Phosphatases - genetics; Dual-Specificity Phosphatases - metabolism; Gene sequencing; Human pathology; Humanities and Social Sciences; 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; multidisciplinary; Peripheral blood; Phenotypes; Phosphatase; Phosphorylation; Receptors, Antigen, T-Cell - metabolism; Regulatory mechanisms (biology); Regulatory sequences; Residues; Science; Science (multidisciplinary); Sequence analysis; T cell receptors; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44843-w

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. The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.