HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs.
BACKGROUND
The structural proteins of human immunodeficiency virus type 1 (HIV-1) are encoded by intron-containing mRNAs that normally are retained in the nucleus. A viral regulatory protein, Rev, specifically induces the accumulation of these transcripts in the cytoplasm. Rev is an RNA-binding protein that also contains an 'effector' domain. The Rev effector domain has recently been shown to function as an autonomous nuclear export signal (NES) that, when fused to a foreign protein, will cause its rapid nuclear export. We and others have recently reported the cloning of a human protein (hRIP/Rab), that specifically interacts with the effector domain of Rev.


RESULTS
Here we show that the NESs contained within two cellular proteins, PKI and I kappa B, which are not involved in RNA metabolism, also interact with hRIP. Fusion of these cellular sequences to the Rev RNA-binding domain reconstitutes a functional Rev protein. In addition to hRIP, these NESs also bind to several nuclear pore complex (NPC). We show that this protein export pathway is highly conserved by demonstrating that mammalian NESs also function in yeast.


CONCLUSIONS
Our results indicate that the HIV-1 Rev protein evolved to take advantage of a cellular protein export pathway in order to allow the nucleocytoplasmic transport of unspliced viral RNA. Our data suggest a model in which the export substrate is translocated through the NPC by sequential interactions with different nucleoporins. Finally, our experiment suggests a mechanism by which I kappa B can downregulate nuclear NF kappa B activity by causing its rapid export from the nucleus.
Fritz
C C
CC
Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester 01605, USA.
Green
M R
MR
D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D015694:Gene Products, rev / Q000235:genetics / Q000378:metabolism*; D016370:Gene Products, rex / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D009685:Nuclear Envelope / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D054321:rev Gene Products, Human Immunodeficiency Virus
C119724:AGFG1 protein, human; D002352:Carrier Proteins; D015694:Gene Products, rev; D016370:Gene Products, rex; D020672:I-kappa B Proteins; D028861:Nuclear Pore Complex Proteins; D011518:Proto-Oncogene Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus; D017868:Cyclic AMP-Dependent Protein Kinases