MoBio The Role of HIV rev Protein Chapter 5

The major role of rev is to regulate the expression of HIV proteins by controlling the export rate of mRNAs. The HIV mRNAs are produced from the primary transcript by three different splicings: unspliced, singly spliced and doubly spliced. Although unspliced and singly sliced mRNAs are made before doubly spliced mRNAs, the protein products of the doubly spliced mRNAs are the first synthesized in the cytoplasm because they are smaller and exported faster. As a matter of fact, expression of unspliced and singly sliced mRNAs would be negligible without the rev protein which is a product of the doubly spliced mRNA.

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Figure 5-B-2. The role of the HIV rev protein.
(a) The rev protein is a product of the doubly spliced mRNA. Without rev, export of unspliced and singly spliced mRNAs (I and II) is very slow.
(b) The rev protein can bind to the rev-response-element (RRE) of mRNA I and II, accelerating their export.
(c) Sequences of NLS and NES in the rev proten.

A rev protein consists of 116 amino acids, including a nuclear localization sequence (NLS) and a nuclear export sequence (NES). The 3D structure of rev is not known yet. However, the hydrophilic NLS is likely to be more exposed than the hydrophobic NES. Therefore, when rev is synthesized in the cytoplasm, the importin α/β may bind to its NLS, carrying it into the nucleus. Even if NLS and NES are equally exposed, the action of Ran still favors the binding of the cytoplasmic rev to importin, rather than exportin.

When rev is in the nucleus, it can bind to mRNA's RRE. The RNA binding domain of rev is in the same region as NLS. Thus, upon binding to mRNA, the NLS of rev is masked, exposing only NES. This facilitates the export of the rev/mRNA complex by the exportin Crm1.