| Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63. | |
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MedLine Citation:
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PMID: 20976196 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Leishmania parasites have evolved sophisticated mechanisms to subvert macrophage immune responses by altering the host cell signal transduction machinery, including inhibition of JAK/STAT signalling and other transcription factors such as AP-1, CREB and NF-κB. AP-1 regulates pro-inflammatory cytokines, chemokines and nitric oxide production. Herein we show that upon Leishmania infection, AP-1 activity within host cells is abolished and correlates with lower expression of 5 of the 7 AP-1 subunits. Of interest, c-Jun, the central component of AP-1, is cleaved by Leishmania. Furthermore, the cleavage of c-Jun is dependent on the expression and activity of the major Leishmania surface protease GP63. Immunoprecipitation of c-Jun from nuclear extracts showed that GP63 interacts, and cleaves c-Jun at the perinuclear area shortly after infection. Phagocytosis inhibition by cytochalasin D did not block c-Jun down-regulation, suggesting that internalization of the parasite might not be necessary to deliver GP63 molecules inside the host cell. This observation was corroborated by the maintenance of c-Jun cleavage upon incubation with L. mexicana culture supernatant, suggesting that secreted, soluble GP63 could use a phagocytosis-independent mechanism to enter the host cell. In support of this, disruption of macrophage lipid raft microdomains by Methyl β-Cyclodextrin (MβCD) partially inhibits the degradation of full length c-Jun. Together our results indicate a novel role of the surface protease GP63 in the Leishmania-mediated subversion of host AP-1 activity. |
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Authors:
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Irazú Contreras; María Adelaida Gómez; Oliver Nguyen; Marina T Shio; Robert W McMaster; Martin Olivier |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-14 |
Journal Detail:
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Title: PLoS pathogens Volume: 6 ISSN: 1553-7374 ISO Abbreviation: PLoS Pathog. Publication Date: 2010 |
Date Detail:
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Created Date: 2010-10-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101238921 Medline TA: PLoS Pathog Country: United States |
Other Details:
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Languages: eng Pagination: e1001148 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada. |
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
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