Home Blog of Signal Transduction Ubiquitin DUB USP9x promotes CD8 + T-cell dysfunction in association with autophagy inhibition in septic liver injury

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USP9x promotes CD8 + 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 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.

 

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In this study, the researchers investigated the role of USP9x, a deubiquitinase required for T-cell development, in hepatic CD8+ T-cell dysfunction in septic mice. Sepsis is a life-threatening condition characterized by inflammation and immunosuppression, and the researchers focused on the impact of sepsis on liver injury.

The researchers found that septic patients with liver injury had decreased CD8+ T cells in their blood compared to those without liver injury, as well as increased CD4/CD8 ratios and downregulated levels of cytolytic factors granzyme B and perforin. In a mouse model of sepsis induced by cecal ligation and puncture, the number of hepatic CD8+ T cells and expression of USP9x both increased 24 hours after sepsis induction, similar to liver injury.

The researchers proposed that USP9x promotes CD8+ T-cell dysfunction and suppresses cell cytolytic activity via inhibition of autophagy. This mechanism was reversed by treatment with the USP9x inhibitor WP1130. The researchers also found that autophagy was significantly increased in hepatic CD8+ T cells of septic mice with conditional knockout of mammalian target of rapamycin.

Overall, this study suggests that USP9x could be a potential therapeutic target for septic liver injury, as it plays a role in promoting CD8+ T-cell dysfunction via autophagy inhibition.

Related Products

Cat.No. Product Name Information
S2243 Degrasyn (WP1130) Degrasyn (WP1130) is a selective deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14, and UCH37) inhibitor and also suppresses Bcr/Abl, also a JAK2 transducer (without affecting 20S proteasome) and activator of transcription (STAT). Degrasyn (WP1130) induces apoptosis and blocks autophagy.

Related Targets

DUB Bcr-Abl Autophagy Apoptosis related