DMCA
Leishmania-Induced Inactivation of the Macrophage Transcription Factor AP-1 Is Mediated by the Parasite
BibTeX
@MISC{Gp_leishmania-inducedinactivation,
author = {Metalloprotease Gp and Irazú Contreras and María Adelaida Gómez and Oliver Nguyen and Marina T. Shio and Robert W. Mcmaster and Martin Olivier},
title = {Leishmania-Induced Inactivation of the Macrophage Transcription Factor AP-1 Is Mediated by the Parasite},
year = {}
}
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Abstract
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-kB. 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 b-Cyclodextrin (MbCD) partially inhibits the degradation of full length c-Jun. Together our
Keyphrases
leishmania-induced inactivation host cell macrophage transcription factor ap-1 gp63 interacts macrophage immune response perinuclear area gp63 molecule mexicana culture supernatant c-jun cleavage major leishmania surface protease gp63 jak stat signalling leishmania infection leishmania parasite c-jun down-regulation methyl b-cyclodextrin nitric oxide production transcription factor macrophage lipid raft microdomains full length c-jun phagocytosis-independent mechanism ap-1 activity pro-inflammatory cytokine ap-1 subunit sophisticated mechanism host cell signal transduction machinery soluble gp63 central component phagocytosis inhibition nuclear extract
