Npc

of mRNP export mediated by a protein encoded by human immunodeficiency virus (HIV).

A retrovirus, HIV integrates a DNA copy of its RNA genome into the host-cell DNA (see Figure 4-43). The integrated viral DNA, or provirus, contains a single transcription unit, which is transcribed into a single primary transcript by cellular RNA polymerase II. The HIV transcript can be spliced in alternative ways to yield three classes of mRNAs: a 9-kb unspliced mRNA; «4-kb mRNAs formed by removal of one intron; and «2-kb mRNAs formed by removal of two or more introns (Figure 12-26). After their synthesis in the host-cell nucleus, all three classes of HIV mRNAs are transported to the cytoplasm and translated into viral proteins; some of the 9-kb unspliced RNA is used as the viral genome in progeny virions that bud from the cell surface.

Since the 9-kb and 4-kb HIV mRNAs contain splice sites, they can be viewed as incompletely spliced mRNAs. However, as discussed earlier, association of such incompletely spliced mRNAs with snRNPs in spliceosomes normally blocks their export from the nucleus. Thus HIV, as well as other retro-viruses, must have some mechanism for overcoming this block, permitting export of the longer viral mRNAs. Some retro-viruses have evolved a sequence called the constitutive transport element (CTE) that binds to the mRNA-exporter with high affinity, thereby permitting export of unspliced retroviral RNA into the cytoplasm. HIV solved the problem differently.

Studies with HIV mutants showed that transport of unspliced 9-kb and singly spliced 4-kb viral mRNAs from the nucleus to the cytoplasm requires the virus-encoded Rev protein. Subsequent biochemical experiments demonstrated that Rev binds to a specific Rev-response element (RRE) present in HIV RNA. In cells infected with HIV mutants lacking the RRE, unspliced and singly spliced viral mRNAs remain in the nucleus, demonstrating that the RRE is required for Rev-mediated stimulation of transport. Rev contains a leucine-rich NES that interacts with exportin 1 complexed with Ran-GTP. As a result, Rev exports unspliced and singly spliced HIV mRNAs through interactions with exportin 1 and the nuclear pore complex.

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