Nef-induced alteration of the early/recycling endosomal compartment correlates with enhancement of HIV-1 infectivity.
human immunodeficiency virus type 1 (HIV-1) Nef interacts with the clathrin-associated AP-1 and AP-3 adaptor complexes, stabilizing their association with endosomal membranes. These findings led us to hypothesize a general impact of this viral protein on the endosomal system. Here, we have shown that Nef specifically disturbs the morphology of the early/recycling compartment, inducing a redistribution of early endosomal markers and a shortening of the tubular recycling endosomal structures. Furthermore, Nef modulates the trafficking of the transferrin receptor (TfR), the prototypical recycling surface protein, indicating that it also disturbs the function of this compartment. Nef reduces the rate of recycling of TfR to the plasma membrane, causing TfR to accumulate in early endosomes and reducing its expression at the cell surface. These effects depend on the leucine-based motif of Nef, which is required for the membrane stabilization of AP-1 and AP-3 complexes. Since we show that this motif is also required for the full infectivity of HIV-1 virions, these results indicate that the positive influence of Nef on viral infectivity may be related to its general effects on early/recycling endosomal compartments.
Madrid
Ricardo
R
Institut Cochin, Department of Infectious Diseases, INSERM U567, CNRS UMR8104, Université Paris 5, 75014 Paris, France.
Janvier
Katy
K
Hitchin
Douglas
D
Day
John
J
Coleman
Scott
S
Noviello
Colleen
C
Bouchet
Jerome
J
Benmerah
Alexandre
A
Guatelli
John
J
Benichou
Serge
S
D020816:Amino Acid Motifs; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D015693:Gene Products, nef / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007930:Leucine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D011990:Receptors, Transferrin / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus
D002966:Clathrin; D015693:Gene Products, nef; D011990:Receptors, Transferrin; D014168:Transferrin; D054311:nef Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors; D007930:Leucine