The HIV-1 protein Vpr impairs phagosome maturation by controlling microtubule-dependent trafficking.
Human immunodeficiency virus type 1 (HIV-1) impairs major functions of macrophages but the molecular basis for this defect remains poorly characterized. Here, we show that macrophages infected with HIV-1 were unable to respond efficiently to phagocytic triggers and to clear bacteria. The maturation of phagosomes, defined by the presence of late endocytic markers, hydrolases, and reactive oxygen species, was perturbed in HIV-1-infected macrophages. We showed that maturation arrest occurred at the level of the EHD3/MICAL-L1 endosomal sorting machinery. Unexpectedly, we found that the regulatory viral protein (Vpr) was crucial to perturb phagosome maturation. Our data reveal that Vpr interacted with EB1, p150(Glued), and dynein heavy chain and was sufficient to critically alter the microtubule plus end localization of EB1 and p150(Glued), hence altering the centripetal movement of phagosomes and their maturation. Thus, we identify Vpr as a modulator of the microtubule-dependent endocytic trafficking in HIV-1-infected macrophages, leading to strong alterations in phagolysosome biogenesis.
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Audrey
A
Dumas
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Gabrielle
G
Lê-Bury
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Florence
F
Marie-Anaïs
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Floriane
F
Herit
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Julie
J
Mazzolini
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Thomas
T
Guilbert
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Pierre
P
Bourdoncle
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
David G
DG
Russell
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Serge
S
Benichou
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
Ahmed
A
Zahraoui
Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France Centre National de la Recherche Scientifique UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France florence.niedergang@inserm.fr.
Florence
F
Niedergang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D010587:Phagocytosis / Q000276:immunology* / Q000502:physiology; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D000096985:Calponins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000072159:Dynactin Complex; D004398:Dyneins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D006899:Mixed Function Oxygenases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D054325:vpr Gene Products, Human Immunodeficiency Virus; C000606360:DCTN1 protein, human; C406447:EHD3 protein, human; C500985:MAPRE1 protein, human; C514912:vpr protein, Human immunodeficiency virus 1; C455272:MICAL1 protein, human; D000096985:Calponins