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MAGRSGDSDE ELLKAVRLIK FLYQSNPPPN PEGTRQARRN RRRRWRERQR QIHSISERIL - 60
STYLGRSAEP VPLQLPPLER LTLDCNEDCG TSGTQGVGSP QILVESPTIL ESGAKE

The Rev protein of human immunodeficiency virus type 1 (HIV-1) is a 116-amino-acid phosphoprotein that is essential for expression of the incompletely spliced mRNAs encoding the structural viral proteins. Direct interaction of Rev with a stem-loop structure termed the Rev-responsive element (RRE) located in this subset of mRNAs protects them from splicing and degradation, facilitates their nuclear-cytoplasmic transport, and promotes their utilization in the cytoplasm. Although Rev is detected primarily in the nuclei and nucleoli of human cells under steady-state conditions, it is known to shuttle between the nucleus and the cytoplasm, thereby supporting the efficient expression of the late viral enzymatic and structural proteins encoded by these mRNAs. In addition to accumulating in nucleoli, Rev has been demonstrated to partially colocalize with the splicing factor SC35 in nuclear speckles or in the vicinity of nuclear speckles. Escorts unspliced or incompletely spliced viral pre-mRNAs (late transcripts) out of the nucleus of infected cells. These pre-mRNAs carry a recognition sequence called Rev responsive element (RRE) located in the env gene, that is not present in fully spliced viral mRNAs (early transcripts). This function is essential since most viral proteins are translated from unspliced or partially spliced pre-mRNAs which cannot exit the nucleus by the pathway used by fully processed cellular mRNAs. Rev itself is translated from a fully spliced mRNA that readily exits the nucleus. Rev's nuclear localization signal (NLS) binds directly to KPNB1/Importin beta-1 without previous binding to KPNA1/Importin alpha-1. KPNB1 binds to the GDP bound form of RAN (Ran-GDP) and targets Rev to the nucleus. In the nucleus, the conversion from Ran-GDP to Ran-GTP dissociates Rev from KPNB1 and allows Rev's binding to the RRE in viral pre-mRNAs. Rev multimerization on the RRE via cooperative assembly exposes its nuclear export signal (NES) to the surface. Rev can then form a complex with XPO1/CRM1 and Ran-GTP, leading to nuclear export of the complex. Conversion from Ran-GTP to Ran-GDP mediates dissociation of the Rev/RRE/XPO1/RAN complex, so that Rev can return to the nucleus for a subsequent round of export. Beside KPNB1, also seems to interact with TNPO1/Transportin-1, RANBP5/IPO5 and IPO7/RANBP7 for nuclear import. The nucleoporin-like HRB/RIP is an essential cofactor that probably indirectly interacts with Rev to release HIV RNAs from the perinuclear region to the cytoplasm.