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

Ghosh, Swagata; Farr, Laura; Singh, Aditya; Leaton, Laura-Ann; Padalia, Jay; Sullivan, David J.; Moonah, Shannon

doi:10.1101/2020.03.24.004531

Cited by 5 publications

(4 citation statements)

References 48 publications

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“…Recently, Klebsiella pneumoniae was found to prevent the neddylation of Cullin1 of the ubiquitin ligase E3-SCF-TrCP complex by inducing CSN5 expression (60). CSN5 is also an important regulator of parasite protein degradation and participates in the effect of zinc ditiocarb against Entamoeba histolytica (61). Our results proved that silencing the Csn5 gene facilitated ROS induction and increased bactericidal capacity in mouse PMs.…”

Section: Discussionsupporting

confidence: 62%

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production

Xiu

Peng

Huang

et al. 2021

The Journal of Immunology

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Neddylation, a posttranslational modification in which NEDD8 is covalently attached to target proteins, has emerged as an endogenous regulator of innate immunity. However, the role of neddylation in methicillin-resistant Staphylococcus aureus (MRSA) infection remains unknown. In this study, we found that neddylation was activated after MRSA infection in vivo and in vitro. Inhibition of neddylation with MLN4924 promoted injury of liver and kidneys in C57BL/6 mice with MRSA bloodstream infection and increased mortality. Blockade of neddylation, either pharmacologically (MLN4924, DI591) or through the use of Uba3 small interfering RNA, inhibited Cullin3 neddylation and promoted Nrf2 accumulation, thus reducing reactive oxygen species (ROS) induction and bacterial killing ability in mouse peritoneal macrophages. In summary, our findings suggest that activation of neddylation in macrophages plays a critical protective role against MRSA infection by increasing ROS production, partially by signaling through the NEDD8-Cullin3-Nrf2-ROS axis. Furthermore, our results may provide a new non-antibiotic treatment strategy for MRSA infection through targeting of neddylation.

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Section: Discussionsupporting

confidence: 62%

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production

Xiu

Peng

Huang

et al. 2021

The Journal of Immunology

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“…This alone does not exclude their presence in the CSN complex, but additional co-immunoprecipitation assays will be required to determine whether they are bona fide CSN components. Interestingly, CSN4 and CSN8 were also not detected in a study of the CSN in Entamoeba histolytica [65], whereas all 8 were detected in another protist, the social amoeba Dictyostelium [66]. Structural studies in other organisms reveal that the CSN covers a large fraction of one face of the SCF, thereby interfering interactions with ubiquitin E2 ligase and SCF target substrate [67].…”

Section: Discussionmentioning

confidence: 98%

Toxoplasma gondiiF-Box Protein L2 Silences Feline-Restricted Genes Necessary for Sexual Commitment

Baptista,

Hosking,

Gas-Pascual

et al. 2023

Preprint

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Toxoplasma gondiiis a foodborne pathogen that can cause severe and life-threatening infections in fetuses and immunocompromised patients. Felids are its only definitive hosts, and a wide range of animals, including humans, serve as intermediate hosts. When the transmissible bradyzoite stage is orally ingested by felids, they transform into merozoites that expand asexually, ultimately generating millions of gametes for the parasite sexual cycle. However, bradyzoites in intermediate hosts differentiate exclusively to disease-causing tachyzoites, which rapidly disseminate throughout the host. Though tachyzoites are well-studied, the molecular mechanisms governing transitioning between developmental stages are poorly understood. Each parasite stage can be distinguished by a characteristic transcriptional signature, with one signature being repressed during the other stages. Switching between stages requires substantial changes in the proteome, which is achieved in part by ubiquitination. F-box proteins mediate protein poly-ubiquitination by recruiting substrates to SKP1, Cullin-1, F-Box protein E3 ubiquitin ligase (SCF-E3) complexes. We have identified an F-box protein namedToxoplasma gondiiF-Box Protein L2 (TgFBXL2), which localizes to distinct nuclear sites. TgFBXL2 is stably engaged in an SCF-E3 complex that is surprisingly also associated with a COP9 signalosome complex that negatively regulates SCF-E3 function. At the cellular level, TgFBXL2-depleted parasites are severely defective in centrosome replication and daughter cell development. Most remarkable, RNA seq data show that TgFBXL2 conditional depletion induces the expression of genes necessary for sexual commitment. We suggest that TgFBXL2 is a latent guardian of sexual stage development inToxoplasmaand poised to remove conflicting proteins in response to an unknown trigger of sexual development.AUTHOR SUMMARYToxoplasma gondiiis a protozoan parasite that replicates sexually in felids and asexually in nearly all other mammals with each life stage having a specific transcriptional profile. When life stage specific transcription is not properly controlled, the parasite dies and therefore it’s important to understand what inhibits expression of sexual stage genes during asexual growth and vice versa. Here we identify a ubiquitin E3 ligase complex that inhibits sexual stage gene expression during asexual growth.

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“…Potent anticancer dithiocarbamates have been identified with a variety of mechanisms of action, including DNA intercalation, inhibition of DNA topoisomerase I and II, and inhibition of other essential kinases (33). Several studies have found diethyldithiocarbamate (DEDC) to be a potent antifungal, antibiotic, and antiparasitic agent (17, 34, 35). One potential mechanism of action by which dithiocarbamate compounds can execute antibiotic activity is through transporting divalent metal ions into bacterial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, there has been a growing body of evidence for the antimicrobial properties of disulfiram's metabolites. In 2020, a group led by Ghosh et al identified Zn 2+diethyldithiocarbamate as a potent antiparasitic agent against Entamoeba histolytica and other parasites (17). In 2021, our group performed a targeted antimicrobial drug screen involving dithiocarbamate compounds (18).…”

Section: Introductionmentioning

confidence: 99%

Compounds derived from N,N-dimethyldithiocarbamate are effective copper-dependent antimicrobials against Streptococcus pneumoniae

Johnson

Menghani

Sanchez-Rosario

et al. 2022

Preprint

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N,N-dimethyldithiocarbamate (DMDC) is a potent copper-dependent antimicrobial against several pathogens, including Streptococcus pneumoniae. Despite the availability of several vaccines against multiple disease-causing strains of S. pneumoniae, the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. We derived novel compounds from DMDC and tested their effectiveness as copper-dependent antimicrobials against S. pneumoniae through in vitro growth and killing curves. Compounds that caused a growth defect and were bactericidal in vitro were tested against other strains of S. pneumoniae and in complex with different transition metals. We found two compounds, sodium N-benzyl-N-methyldithiocarbamate and sodium N-allyl-N-methyldithiocarbamate (herein "Compound 3" and "Compound 4"), were effective against TIGR4, D39, and ATCC® 6303™ (a type 3 capsular strain) and further increased the internal concentrations of copper to the same previously reported levels as with DMDC and copper treatment. We found that both Compound 3 and Compound 4 were bacteriostatic in combination with zinc. We tested Compound 3 and Compound 4 in vivo against a murine pneumonia model, finding that Compound 3, and not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of S. pneumoniae-infected mice. We found that the combination of Compound 3 and copper made the pneumococcus more susceptible to activated macrophage mediated killing via an in vitro macrophage killing assay. Collectively, we demonstrate that derivatizing DMDC holds promise as potent bactericidal antibiotics against S. pneumoniae.

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

Cited by 5 publications

References 48 publications

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production

Toxoplasma gondiiF-Box Protein L2 Silences Feline-Restricted Genes Necessary for Sexual Commitment

Compounds derived from N,N-dimethyldithiocarbamate are effective copper-dependent antimicrobials against Streptococcus pneumoniae

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