title: Impact of Leishmania infection on host macrophage nuclear physiology and nucleopore complex integrity.
abstract: The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF-κB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites.
authors.affiliation: Departments of Medicine and Microbiology & Immunology, The Research Institute of the McGill University Health Centre, McGill University, Montréal, Quebec, Canada.
authors.forename: Amandine
authors.initials: A
authors.lastname: Isnard
authors.affiliation: Departments of Medicine and Microbiology & Immunology, The Research Institute of the McGill University Health Centre, McGill University, Montréal, Quebec, Canada.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Christian
authors.affiliation: Department of Physiology, McGill University, Montréal, Quebec, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kodiha
authors.affiliation: Department of Physiology, McGill University, Montréal, Quebec, Canada.
authors.forename: Ursula
authors.initials: U
authors.lastname: Stochaj
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
authors.affiliation: Departments of Medicine and Microbiology & Immunology, The Research Institute of the McGill University Health Centre, McGill University, Montréal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D007891:Leishmania / Q000235:genetics / Q000378:metabolism*; D007896:Leishmaniasis / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D022022:Nuclear Pore / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D018808:Transcription Factor AP-1; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania
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