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 as Leishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causing Entamoeba histolytica...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1008952 |
| _version_ | 1818736065416003584 |
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| author | Swagata Ghosh Laura Farr Aditya Singh Laura-Ann Leaton Jay Padalia Debbie-Ann Shirley David Sullivan Shannon Moonah |
| author_facet | Swagata Ghosh Laura Farr Aditya Singh Laura-Ann Leaton Jay Padalia Debbie-Ann Shirley David Sullivan Shannon Moonah |
| author_sort | Swagata Ghosh |
| collection | DOAJ |
| description | 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 as Leishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causing Entamoeba histolytica to study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption of E. histolytica CSN 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. |
| first_indexed | 2024-12-18T00:31:13Z |
| format | Article |
| id | doaj.art-05fefe0281184bfd8ff2bab4e90b6608 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-18T00:31:13Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-05fefe0281184bfd8ff2bab4e90b66082022-12-21T21:27:08ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742020-09-01169e100895210.1371/journal.ppat.1008952COP9 signalosome is an essential and druggable parasite target that regulates protein degradation.Swagata GhoshLaura FarrAditya SinghLaura-Ann LeatonJay PadaliaDebbie-Ann ShirleyDavid SullivanShannon MoonahUnderstanding 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 as Leishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causing Entamoeba histolytica to study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption of E. histolytica CSN 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.https://doi.org/10.1371/journal.ppat.1008952 |
| spellingShingle | Swagata Ghosh Laura Farr Aditya Singh Laura-Ann Leaton Jay Padalia Debbie-Ann Shirley David Sullivan Shannon Moonah COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. PLoS Pathogens |
| title | COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |
| title_full | COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |
| title_fullStr | COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |
| title_full_unstemmed | COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |
| title_short | COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |
| title_sort | cop9 signalosome is an essential and druggable parasite target that regulates protein degradation |
| url | https://doi.org/10.1371/journal.ppat.1008952 |
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