COP9 signalosome is an essential and druggable parasite target that regulates protein degradation

Understanding how the protozoan protein degradation pathway is regulated could uncover new parasite biology for drug discovery. We found the COP9 signalosome (CSN) conserved in multiple pathogens such asLeishmania,Trypanosoma,Toxoplasma, and used the severe diarrhea-causingEntamoeba histolyticato study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption ofE.histolyticaCSN by two distinct approaches inhibited cell proliferation and viability. Both CSN5 knockdown and dominant negative mutation trapped cullin in a neddylated state, disrupting UPS activity and protein degradation. In addition, zinc ditiocarb (ZnDTC), a main metabolite of the inexpensive FDA-approved globally-available drug disulfiram, was active against parasites acting in a COP9-dependent manner. ZnDTC, given as disulfiram-zinc, had oral efficacy in clearing parasites in vivo. Our findings provide insights into the regulation of parasite protein degradation, and supports the significant therapeutic potential of COP9 inhibition. Author summary Protozoan parasites continue to pose a serious threat to health worldwide, which is further compounded by currently unsatisfactory treatment options. While proteasome-mediated protein degradation has received tremendous attention recently in the parasitology field as an attractive drug target, our understanding of how this pathway is regulated in these disease-relevant parasites remains limited. Further understanding could pave the way for new parasite biology and drug discovery. COP9 signalosome was found to be produced by multiple medically important protozoan parasites. We uncovered how the essential protein degradation process is regulated by protozoanEntamoeba histolytica, an important cause of life-threatening diarrhea globally, and found that parasite COP9 signalosome shows significant potential as a therapeutic target.