Post-transcriptional Regulation of HTLV Gene Expression: Rex to the Rescue

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) and other members of the Deltaretrovirus genus code for a regulatory protein named Rex that binds to the Rex-responsive element present on viral mRNAs. Rex rescues viral mRNAs from complete splicing or degradation and guides them to the cytoplasm for translation. The activity of Rex is essential for expression of viral transcripts coding for the virion components and thus represents a potential target for virus eradication. We present an overview of the functional properties of the HTLV-1 and HTLV-2 Rex proteins (Rex-1 and Rex-2), outline mechanisms controlling Rex function, and discuss similarities and differences in the sequences of Rex coded by HTLV-1, -2, -3, and -4 that may influence their molecular anatomy and functional properties.

Keywords: HTLV-1; HTLV-2; RNA export; Rex; splicing.

FIGURE 1

Functional activities described for Rex. See text for description. Interference with NMD and Dicer were described for Rex-1. The figure was made using SMART images (https://smart.servier.com).

FIGURE 2

Domain structure and sequence comparison of HTLV Rex proteins. (A) shows the functional domain structure of Rex-1 and Rex-2. Positions of phosphoacceptor sites identified in Rex-1 (ATK-1) (Kesic et al., 2009a) and Rex-2 (Mo) (Kesic et al., 2009b) are indicated in red type. Diagrams are modified from Kesic et al. (2009a, . (B) shows a multiple sequence alignment of Rex proteins obtained with Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/). Amino acids are labeled in different colors according to their biochemical properties (red, small/hydrophobic; blue, acidic; magenta, basic; green, hydroxyl/sulfhydryl/amine/Glycine). Asterisks indicate single conserved residues; and periods indicate residues with similar properties. GenBank Accession IDs: HTLV-1 (ATK-1): J02029.1; HTLV-2 (Mo): M10060.1; HTLV-3 (Pyl 43): DQ462191.1; HTLV-4 (1863LE): EF488483.1 (see also Supplementary Figure 1). Tables in (C) show conservation of the indicated serines and threonines in Rex-1 and Rex-2 proteins coded by the panel of 28 viral isolates listed in Supplementary Table 1.

FIGURE 3

Rex isoforms coded by HTLV-1 (A) and HTLV-2 (B). mRNAs coding for Tax/Rex and Rex isoforms are indicated on the left. The Tax and Rex ORFs are indicated by yellow and blue boxes, respectively, and the HTLV-2 p28 (x-II) ORF is indicated by a light purple box. The domain structures of Rex isoforms are indicated on the right. The red X indicates a stop codon upstream of the exon 3 splice acceptor that is in frame with the Tax ORF. p16Rex is a very low-abundance truncated Rex-2 isoform (Ciminale et al., 1995).

FIGURE 4

Factors controlling Rex function. Summarized are factors that promote (→) and interfere with (⊣) Rex function, as described in the text.