HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs

Background: The structural proteins oi human immunodeficiency virus type I (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 ?unction 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 oi 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 proteins located an the nucleoplasmic, membrane, and cytoplasmic side of the 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 experiments suggest a mechanism by which I kappa B can downregulate nuclear NF kappa B activity by causing its rapid export from the nucleus.