Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation
Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were...
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MDPI AG
2021-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/1/105 |
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| author | Ji Yeon Lee Eun-Koung An Juyoung Hwang Jun-O. Jin Peter C. W. Lee |
| author_facet | Ji Yeon Lee Eun-Koung An Juyoung Hwang Jun-O. Jin Peter C. W. Lee |
| author_sort | Ji Yeon Lee |
| collection | DOAJ |
| description | Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated in T cells by toll-like receptor agonists and anti-CD3/28 antibody stimulation, but not in dendritic cells, macrophages, B cells, and natural killer cells. Additionally, we generated T cell-specific UBA6-deficient mice and found that UBA6-deficient CD4 and CD8 T cells elevated the production of interferon-gamma (IFN-γ). Moreover, the transfer of UBA6-deficient CD4 and CD8 T cells in RAG1-knockout mice exacerbated the development of multi-organ inflammation compared with control CD4 and CD8 T cell transfer. In human peripheral blood CD4 and CD8 T cells, basal levels of UBA6 in lupus patients presented much lower than those in healthy controls. Moreover, the IFN-γ production efficiency of CD4 and CD8 T cells was negatively correlated to UBA6 levels in patients with lupus. Finally, we found that the function of UBA6 was mediated by destabilization of IκBα degradation, thereby increasing NF-κB p65 activation in the T cells. Our study identifies UBA6 as a critical regulator of IFN-γ production in T cells by modulating the NF-κB p65 activation pathway. |
| first_indexed | 2024-03-10T03:46:24Z |
| format | Article |
| id | doaj.art-6cbd907e5e384c6c88abc8fac0432cc8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:46:24Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-6cbd907e5e384c6c88abc8fac0432cc82023-11-23T11:20:16ZengMDPI AGCells2073-44092021-12-0111110510.3390/cells11010105Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell DifferentiationJi Yeon Lee0Eun-Koung An1Juyoung Hwang2Jun-O. Jin3Peter C. W. Lee4Division of Rheumatology, Department of Medicine, Seoul St. Mary’s Hospital, Catholic University, Seoul 06591, KoreaDepartment of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, KoreaDepartment of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, KoreaDepartment of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, KoreaDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, KoreaUbiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated in T cells by toll-like receptor agonists and anti-CD3/28 antibody stimulation, but not in dendritic cells, macrophages, B cells, and natural killer cells. Additionally, we generated T cell-specific UBA6-deficient mice and found that UBA6-deficient CD4 and CD8 T cells elevated the production of interferon-gamma (IFN-γ). Moreover, the transfer of UBA6-deficient CD4 and CD8 T cells in RAG1-knockout mice exacerbated the development of multi-organ inflammation compared with control CD4 and CD8 T cell transfer. In human peripheral blood CD4 and CD8 T cells, basal levels of UBA6 in lupus patients presented much lower than those in healthy controls. Moreover, the IFN-γ production efficiency of CD4 and CD8 T cells was negatively correlated to UBA6 levels in patients with lupus. Finally, we found that the function of UBA6 was mediated by destabilization of IκBα degradation, thereby increasing NF-κB p65 activation in the T cells. Our study identifies UBA6 as a critical regulator of IFN-γ production in T cells by modulating the NF-κB p65 activation pathway.https://www.mdpi.com/2073-4409/11/1/105UBA6T cellubiquitindifferentiationmultiorgan inflammation |
| spellingShingle | Ji Yeon Lee Eun-Koung An Juyoung Hwang Jun-O. Jin Peter C. W. Lee Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation Cells UBA6 T cell ubiquitin differentiation multiorgan inflammation |
| title | Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation |
| title_full | Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation |
| title_fullStr | Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation |
| title_full_unstemmed | Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation |
| title_short | Ubiquitin Activating Enzyme UBA6 Regulates Th1 and Tc1 Cell Differentiation |
| title_sort | ubiquitin activating enzyme uba6 regulates th1 and tc1 cell differentiation |
| topic | UBA6 T cell ubiquitin differentiation multiorgan inflammation |
| url | https://www.mdpi.com/2073-4409/11/1/105 |
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