Leishmania-Induced Inactivation of the Macrophage Transcription Factor AP-1 Is Mediated by the Parasite Metalloprotease GP63

PLoS Pathogens

María Adelaida Gómez¹  Marina T. Shio¹  Robert W. McMaster²  Martin Olivier²  Irazú Contreras²  Oliver Nguyen² 

[1] Centre for the Study of Host Resistance and the Research Institute of McGill University Health Centre, Montreal, Quebec, Canada;Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

关键词: Macrophages;    Leishmania;    Parasitic diseases;    Transcription factors;    Leishmania donovani;    Lipids;    Promastigotes;    Sequence motif analysis;   

DOI  :  10.1371/journal.ppat.1001148

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY