The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
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 ubiq...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44843-w |
| _version_ | 1797349785216221184 |
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| author | Ying-Chun Shih Hsueh-Fen Chen Chia-Ying Wu Yi-Ru Ciou Chia-Wen Wang Huai-Chia Chuang Tse-Hua Tan |
| author_facet | Ying-Chun Shih Hsueh-Fen Chen Chia-Ying Wu Yi-Ru Ciou Chia-Wen Wang Huai-Chia Chuang Tse-Hua Tan |
| author_sort | Ying-Chun Shih |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T12:36:31Z |
| format | Article |
| id | doaj.art-74ada20324de4b6ca3ec165d10c91490 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T12:36:31Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-74ada20324de4b6ca3ec165d10c914902024-01-21T12:27:25ZengNature PortfolioNature Communications2041-17232024-01-0115112110.1038/s41467-024-44843-wThe phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signallingYing-Chun Shih0Hsueh-Fen Chen1Chia-Ying Wu2Yi-Ru Ciou3Chia-Wen Wang4Huai-Chia Chuang5Tse-Hua Tan6Immunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesImmunology Research Center, National Health Research InstitutesAbstract 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.https://doi.org/10.1038/s41467-024-44843-w |
| spellingShingle | Ying-Chun Shih Hsueh-Fen Chen Chia-Ying Wu Yi-Ru Ciou Chia-Wen Wang Huai-Chia Chuang Tse-Hua Tan The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling Nature Communications |
| title | The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling |
| title_full | The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling |
| title_fullStr | The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling |
| title_full_unstemmed | The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling |
| title_short | The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling |
| title_sort | phosphatase dusp22 inhibits ubr2 mediated k63 ubiquitination and activation of lck downstream of tcr signalling |
| url | https://doi.org/10.1038/s41467-024-44843-w |
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