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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Ying-Chun Shih & Hsueh-Fen Chen & Chia-Ying Wu & Yi-Ru Ciou & Chia-Wen Wang & Huai-Chia Chuang & Tse-Hua Tan, 2024. "The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44843-w
    DOI: 10.1038/s41467-024-44843-w
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    1. Ju-Pi Li & Chia-Yu Yang & Huai-Chia Chuang & Joung-Liang Lan & Der-Yuan Chen & Yi-Ming Chen & Xiaohong Wang & Alice J. Chen & John W. Belmont & Tse-Hua Tan, 2014. "The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
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