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

Ying-Chun Shih, Hsueh-Fen Chen, Chia-Ying Wu, Yi-Ru Ciou, Chia-Wen Wang, Huai-Chia Chuang () and Tse-Hua Tan ()
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Ying-Chun Shih: National Health Research Institutes
Hsueh-Fen Chen: National Health Research Institutes
Chia-Ying Wu: National Health Research Institutes
Yi-Ru Ciou: National Health Research Institutes
Chia-Wen Wang: National Health Research Institutes
Huai-Chia Chuang: National Health Research Institutes
Tse-Hua Tan: National Health Research Institutes

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44843-w

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