USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury
Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
China Science Publishing & Media Ltd.
2022-11-01
|
| Series: | Acta Biochimica et Biophysica Sinica |
| Subjects: | |
| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2022174 |
| _version_ | 1797635316697268224 |
|---|---|
| author | Sheng Lulu Chen Juntao Tong Yiqing Zhang Yi Feng Qiming Tang Zhenghao |
| author_facet | Sheng Lulu Chen Juntao Tong Yiqing Zhang Yi Feng Qiming Tang Zhenghao |
| author_sort | Sheng Lulu |
| collection | DOAJ |
| description | Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in hepatic CD8 <sup>+</sup> T-cell dysfunction in septic mice. We find that CD8 <sup>+</sup> T cells are decreased in the blood of septic patients with liver injury compared with those without liver injury, the CD4/CD8 ratio is increased, and the levels of cytolytic factors, granzyme B and perforin are downregulated. The number of hepatic CD8 <sup>+</sup> T cells and USP9x expression are both increased <sc>24 h</sc> after cecal ligation and puncture-induced sepsis in a mouse model, a pattern similar to liver injury. The mechanism involves promotion of CD8 <sup>+</sup> T-cell dysfunction by USP9x associated with suppression of cell cytolytic activity via autophagy inhibition, which is reversed by the USP9x inhibitor WP1130. In the in vivo studies, autophagy is significantly increased in hepatic CD8 <sup>+</sup> T cells of septic mice with conditional knockout of mammalian target of rapamycin. This study shows that USP9x has the potential to be used as a therapeutic target in septic liver injury. |
| first_indexed | 2024-03-11T12:20:30Z |
| format | Article |
| id | doaj.art-20181ae3fb0a47179146f9fea5a07182 |
| institution | Directory Open Access Journal |
| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:20:30Z |
| publishDate | 2022-11-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-20181ae3fb0a47179146f9fea5a071822023-11-07T01:02:56ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452022-11-01541765177410.3724/abbs.202217420d259ccUSP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injurySheng Lulu0Chen Juntao1Tong Yiqing2Zhang Yi3Feng Qiming4Tang Zhenghao5["Department of Emergency Medicine, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"]["Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China"]["Department of Emergency Medicine, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"]["Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China","Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]["Department of Emergency Medicine, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"]["Department of Infectious Diseases, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China"]Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in hepatic CD8 <sup>+</sup> T-cell dysfunction in septic mice. We find that CD8 <sup>+</sup> T cells are decreased in the blood of septic patients with liver injury compared with those without liver injury, the CD4/CD8 ratio is increased, and the levels of cytolytic factors, granzyme B and perforin are downregulated. The number of hepatic CD8 <sup>+</sup> T cells and USP9x expression are both increased <sc>24 h</sc> after cecal ligation and puncture-induced sepsis in a mouse model, a pattern similar to liver injury. The mechanism involves promotion of CD8 <sup>+</sup> T-cell dysfunction by USP9x associated with suppression of cell cytolytic activity via autophagy inhibition, which is reversed by the USP9x inhibitor WP1130. In the in vivo studies, autophagy is significantly increased in hepatic CD8 <sup>+</sup> T cells of septic mice with conditional knockout of mammalian target of rapamycin. This study shows that USP9x has the potential to be used as a therapeutic target in septic liver injury. https://www.sciengine.com/doi/10.3724/abbs.2022174sepsisliver injuryUSP9xCD8 <sup>+</sup> T cellsautophagy |
| spellingShingle | Sheng Lulu Chen Juntao Tong Yiqing Zhang Yi Feng Qiming Tang Zhenghao USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury Acta Biochimica et Biophysica Sinica sepsis liver injury USP9x CD8 <sup>+</sup> T cells autophagy |
| title | USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury |
| title_full | USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury |
| title_fullStr | USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury |
| title_full_unstemmed | USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury |
| title_short | USP9x promotes CD8 <sup>+</sup> T-cell dysfunction in association with autophagy inhibition in septic liver injury |
| title_sort | usp9x promotes cd8 sup sup t cell dysfunction in association with autophagy inhibition in septic liver injury |
| topic | sepsis liver injury USP9x CD8 <sup>+</sup> T cells autophagy |
| url | https://www.sciengine.com/doi/10.3724/abbs.2022174 |
| work_keys_str_mv | AT shenglulu usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury AT chenjuntao usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury AT tongyiqing usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury AT zhangyi usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury AT fengqiming usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury AT tangzhenghao usp9xpromotescd8supsuptcelldysfunctioninassociationwithautophagyinhibitioninsepticliverinjury |