CSN1201, a subunit of the COP9 signalosome, regulates the virulence in Cryptococcus neoformans infection

The COP9 signalosome (CSN) is a multisubunit protein complex, and it now has been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. Cryptococcus neoformans (C. neoformans) is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily in the immune compromised population. Here, we generated CSN deletion mutants to investigate the role in Cryptococcus infection. Compared to other CSN mutants, we identified a CSN1201 mutant exhibited severely attenuated virulence. Deletion of CSN1201 made cryptococcal cells more susceptible to nearly all in vitro stresses. Furthermore, deletion of CSN1201 obviously impaired survival of C. neoformans. At the same time, in vivo virulence assay of mouse infection models demonstrated that CSN1201 significantly enhanced the virulence of C. neoformans compared with the other CSN subunit strains, while ELISA analysis of C. neoformans infection in innate or adaptive immune response showed that deletion of CSN1201 significantly impaired cytokines and interferon expression. In vitro model of the blood-brain barrier (BBB) analysis indicated that deletion of CSN1201 reduced the invasion efficacy of Cryptococcusto cross BBB. Taken together, our findings reveal a novel mechanism of CSN1201, which plays a critical role for the virulence composite of C. neoformans, and also provides an additional yeast survival and propagation advantage in the host.