Anti-COPS5 monoclonal antibody, clone 7D4.49

The innate immune response conferred by type I interferons is essential for host defense against viral infection but needs to be tightly controlled to avoid immunopathology. We performed a systematic functional screening by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) knockout and overexpression to investigate the roles of the deubiquitinating enzyme (DUB) family in regulating antiviral immunity. We demonstrated that the expression of a large fraction of DUBs underwent complex temporal alteration, suggesting a dynamic program of feedback regulation. Moreover, we identified previously unrecognized roles of a subset of DUBs, including USP5, USP14, USP22, USP48, USP52, COPS5, and BRCC3, in inhibiting antiviral immunity at various levels. We explored an unexpected mechanism where multiple DUBs, such as USP5 and USP22, form diverse signalosomes with E3 ligases or DUBs to alter the substrates' ubiquitination state instead of directly cleaving the ubiquitin chains on substrates via their protease activity. Altogether, our study has revealed a panoramic view of the broad and dynamic involvement of DUB family proteins in regulating antiviral responses.

Aerobic glycolysis promotes metastasis and correlates with poorer clinical outcomes in hepatocellular carcinoma (HCC), but the controllers and mechanisms of abnormally activated glycolysis remain unclear. Herein, we demonstrated that the fifth component of the constitutive photomorphogenic 9 (COP9) signalosome complex (COPS5/CSN5) was a controller of glycolysis. For the first time, we found that CSN5 could influence the expression of glycolytic metabolism-associated proteins, especially hexokinase 2 (HK2), a glycolytic rate-limiting enzyme. In addition, we found that CSN5 was associated with HK2 overexpression in HCC tissues. Silencing CSN5 expression caused a decrease in the level of the HK2 protein, glucose uptake, glycolysis capacity and the production of glycolytic intermediates in HCC cells. Re-expression of HK2 rescued the decreased glycolytic flux induced by CSN5 knockdown, whereas inhibition of HK2 alleviated CSN5-enhanced glycolysis. Functionally, CSN5 regulated HCC cell invasion and metastasis via HK2-mediated glycolysis. Mechanistically, we demonstrated that CSN5 attenuated the ubiquitin-proteasome system-mediated degradation of HK2 through its deubiquitinase function. Inhibition of CSN5 kinase activity by curcumin decreased HK2 protein expression and glycolysis, repressed the metastasis of HCC cells in vitro and in vivo, and prolonged the survival time of tumor-bearing nude mice. Overall, our study identified CSN5 as a controller of glycolysis, and it may be a potential treatment target for HCC.