A novel nuclear export activity in HIV-1 matrix protein required for viral replication.
An important aspect of the pathophysiology of human immunodeficiency virus type-1 (HIV-1) infection is the ability of the virus to replicate in non-dividing cells. HIV-1 matrix (MA), the amino-terminal domain of the Pr55 gag polyprotein (Pr55), bears a nuclear localization signal that promotes localization of the viral preintegration complex to the nucleus of non-dividing cells following virus entry. However, late during infection, MA, as part of Pr55, directs unspliced viral RNA to the plasma membrane, the site of virus assembly. How MA can mediate these two opposing targeting functions is not understood. Here we demonstrate that MA has a previously undescribed nuclear export activity. Although MA lacks the canonical leucine-rich nuclear export signal, nuclear export is mediated through the conserved Crm1p pathway and functions in both mammalian cells and yeast. A mutation that disrupts the MA nuclear export signal (MA-M4) mislocalizes Pr55 and genomic viral RNA to the nucleus, thereby severely impairing viral replication. Furthermore, we show that MA-M4 can act in a dominant-negative fashion to mislocalize genomic viral RNA even in the presence of wild-type MA. We conclude that the MA nuclear export signal is required to counteract the MA nuclear localization signal, thus ensuring the cytoplasmic availability of the components required for virion assembly.
Dupont
S
S
Howard Hughes Medical Institute and Program in Molecular Medicine at the University of Massachusetts Medical Center, Worcester 01605, USA.
Sharova
N
N
DéHoratius
C
C
Virbasius
C M
CM
Zhu
X
X
Bukrinskaya
A G
AG
Stevenson
M
M
Green
M R
MR
D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology*; D015683:Gene Products, gag / Q000378:metabolism*; D015488:HIV Antigens / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D011498:Protein Precursors / Q000378:metabolism; D021382:Protein Sorting Signals / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D014764:Viral Proteins; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015488:HIV Antigens; D011498:Protein Precursors; D021382:Protein Sorting Signals; D012367:RNA, Viral; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C059767:p55 gag precursor protein, Human immunodeficiency virus 1