HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome
Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus,...
| Published in: | Frontiers in Pharmacology |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-06-01
|
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1191692/full |
| _version_ | 1851901834094968832 |
|---|---|
| author | Junhao Yin Junhao Yin Junhao Yin Junhao Yin Jiabao Xu Jiabao Xu Jiabao Xu Jiabao Xu Changyu Chen Changyu Chen Changyu Chen Changyu Chen Xinyi Ma Xinyi Ma Xinyi Ma Xinyi Ma Hanyi Zhu Hanyi Zhu Hanyi Zhu Hanyi Zhu Lisong Xie Lisong Xie Lisong Xie Lisong Xie Baoli Wang Baoli Wang Baoli Wang Baoli Wang Yanxiong Shao Yanxiong Shao Yanxiong Shao Yanxiong Shao Yijie Zhao Yu Wei Anni Hu Zhanglong Zheng Chuangqi Yu Chuangqi Yu Chuangqi Yu Chuangqi Yu Jiayao Fu Jiayao Fu Jiayao Fu Jiayao Fu Lingyan Zheng Lingyan Zheng Lingyan Zheng Lingyan Zheng |
| author_facet | Junhao Yin Junhao Yin Junhao Yin Junhao Yin Jiabao Xu Jiabao Xu Jiabao Xu Jiabao Xu Changyu Chen Changyu Chen Changyu Chen Changyu Chen Xinyi Ma Xinyi Ma Xinyi Ma Xinyi Ma Hanyi Zhu Hanyi Zhu Hanyi Zhu Hanyi Zhu Lisong Xie Lisong Xie Lisong Xie Lisong Xie Baoli Wang Baoli Wang Baoli Wang Baoli Wang Yanxiong Shao Yanxiong Shao Yanxiong Shao Yanxiong Shao Yijie Zhao Yu Wei Anni Hu Zhanglong Zheng Chuangqi Yu Chuangqi Yu Chuangqi Yu Chuangqi Yu Jiayao Fu Jiayao Fu Jiayao Fu Jiayao Fu Lingyan Zheng Lingyan Zheng Lingyan Zheng Lingyan Zheng |
| author_sort | Junhao Yin |
| collection | DOAJ |
| container_title | Frontiers in Pharmacology |
| description | Introduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology.Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy.Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice.Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment. |
| format | Article |
| id | doaj-art-7d5d19ebb58e4f7eb72cd970f2ade18c |
| institution | Directory of Open Access Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| spelling | doaj-art-7d5d19ebb58e4f7eb72cd970f2ade18c2025-08-19T22:05:33ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-06-011410.3389/fphar.2023.11916921191692HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndromeJunhao Yin0Junhao Yin1Junhao Yin2Junhao Yin3Jiabao Xu4Jiabao Xu5Jiabao Xu6Jiabao Xu7Changyu Chen8Changyu Chen9Changyu Chen10Changyu Chen11Xinyi Ma12Xinyi Ma13Xinyi Ma14Xinyi Ma15Hanyi Zhu16Hanyi Zhu17Hanyi Zhu18Hanyi Zhu19Lisong Xie20Lisong Xie21Lisong Xie22Lisong Xie23Baoli Wang24Baoli Wang25Baoli Wang26Baoli Wang27Yanxiong Shao28Yanxiong Shao29Yanxiong Shao30Yanxiong Shao31Yijie Zhao32Yu Wei33Anni Hu34Zhanglong Zheng35Chuangqi Yu36Chuangqi Yu37Chuangqi Yu38Chuangqi Yu39Jiayao Fu40Jiayao Fu41Jiayao Fu42Jiayao Fu43Lingyan Zheng44Lingyan Zheng45Lingyan Zheng46Lingyan Zheng47Department of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai, ChinaDepartment of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, ChinaDepartment of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, ChinaDepartment of Oral and Maxillofacial Surgery, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaDepartment of Oral Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, ChinaNational Center for Stomatology and National Clinical Research Center for Oral Disease, Shanghai, ChinaShanghai Key Laboratory of Stomatology, Shanghai, ChinaShanghai Institute of Stomatology, Shanghai, ChinaIntroduction: Sjögren’s syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology.Methods: In the context of HUWE1 inhibition, we investigated the impact of the HUWE1 inhibitor BI8626 and sh-Huwe1 on CD4+ T cells in mice, focusing on the assessment of activation levels, proliferation capacity, and cholesterol abundance. Furthermore, we examined the therapeutic potential of BI8626 in NOD/ShiLtj mice and evaluated its efficacy as a treatment strategy.Results: Inhibition of HUWE1 reduces ABCA1 ubiquitination and promotes cholesterol efflux, decreasing intracellular cholesterol and reducing the expression of phosphorylated ZAP-70, CD25, and other activation markers, culminating in the suppressed proliferation of CD4+ T cells. Moreover, pharmacological inhibition of HUWE1 significantly reduces CD4+ T-cell infiltration in the submandibular glands and improves salivary flow rate in NOD/ShiLtj mice.Conclusion: These findings suggest that HUWE1 may regulate CD4+ T-cell activation and SS development by modulating ABCA1-mediated cholesterol efflux and presents a promising target for SS treatment.https://www.frontiersin.org/articles/10.3389/fphar.2023.1191692/fullCD4+ T cellHUWE1ABCA1Sjögren’s syndromecholesterol efflux |
| spellingShingle | Junhao Yin Junhao Yin Junhao Yin Junhao Yin Jiabao Xu Jiabao Xu Jiabao Xu Jiabao Xu Changyu Chen Changyu Chen Changyu Chen Changyu Chen Xinyi Ma Xinyi Ma Xinyi Ma Xinyi Ma Hanyi Zhu Hanyi Zhu Hanyi Zhu Hanyi Zhu Lisong Xie Lisong Xie Lisong Xie Lisong Xie Baoli Wang Baoli Wang Baoli Wang Baoli Wang Yanxiong Shao Yanxiong Shao Yanxiong Shao Yanxiong Shao Yijie Zhao Yu Wei Anni Hu Zhanglong Zheng Chuangqi Yu Chuangqi Yu Chuangqi Yu Chuangqi Yu Jiayao Fu Jiayao Fu Jiayao Fu Jiayao Fu Lingyan Zheng Lingyan Zheng Lingyan Zheng Lingyan Zheng HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome CD4+ T cell HUWE1 ABCA1 Sjögren’s syndrome cholesterol efflux |
| title | HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome |
| title_full | HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome |
| title_fullStr | HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome |
| title_full_unstemmed | HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome |
| title_short | HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4+ T cell activation in Sjögren’s syndrome |
| title_sort | hect uba and wwe domain containing 1 represses cholesterol efflux during cd4 t cell activation in sjogren s syndrome |
| topic | CD4+ T cell HUWE1 ABCA1 Sjögren’s syndrome cholesterol efflux |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1191692/full |
| work_keys_str_mv | AT junhaoyin hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT junhaoyin hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT junhaoyin hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT junhaoyin hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiabaoxu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiabaoxu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiabaoxu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiabaoxu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT changyuchen hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT changyuchen hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT changyuchen hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT changyuchen hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT xinyima hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT xinyima hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT xinyima hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT xinyima hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT hanyizhu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT hanyizhu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT hanyizhu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT hanyizhu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lisongxie hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lisongxie hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lisongxie hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lisongxie hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT baoliwang hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT baoliwang hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT baoliwang hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT baoliwang hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yanxiongshao hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yanxiongshao hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yanxiongshao hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yanxiongshao hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yijiezhao hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT yuwei hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT annihu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT zhanglongzheng hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT chuangqiyu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT chuangqiyu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT chuangqiyu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT chuangqiyu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiayaofu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiayaofu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiayaofu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT jiayaofu hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lingyanzheng hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lingyanzheng hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lingyanzheng hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome AT lingyanzheng hectubaandwwedomaincontaining1repressescholesteroleffluxduringcd4tcellactivationinsjogrenssyndrome |