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+T-cell dysfunction in septic mice.We find that CD8+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+T cells and USP9x expression are both increased 24 h after cecal ligation and puncture-induced sepsis in a mouse model,a pattern similar to liver injury.The mechanism involves promotion of CD8+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+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.

Lulu Sheng;Juntao Chen;Yiqing Tong;Yi Zhang;Qiming Feng;Zhenghao Tang

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;Biomedical Research Center,Institute for Clinical Sciences,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Department of Infectious Diseases,Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200233,China

生物化学与生物物理学报（英文版）

[1]Lulu Sheng;Juntao Chen;Yiqing Tong;Yi Zhang;Qiming Feng;Zhenghao Tang-.USP9x promotes CD8+T-cell dysfunction in association with autophagy inhibition in septic liver injury)[J].生物化学与生物物理学报（英文版）,2022(12):1765-1774

USP9x,cytolytic

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