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Review
. 2015;12(9):942-9.
doi: 10.1080/15476286.2015.1065375.

Insights into the nuclear export of murine leukemia virus intron-containing RNA

Lucie Pessel-Vivares  1   2 , Laurent Houzet  3 , Sébastien Lainé  1 , Marylène Mougel  1
Affiliations
Review

Insights into the nuclear export of murine leukemia virus intron-containing RNA

Lucie Pessel-Vivares et al. RNA Biol. 2015.

Abstract

The retroviral genome consists of an intron-containing transcript that has essential cytoplasmic functions in the infected cell. This viral transcript can escape splicing, circumvent the nuclear checkpoint mechanisms and be transported to the cytoplasm by hijacking the host machinery. Once in the cytoplasm, viral unspliced RNA acts as mRNA to be translated and as genomic RNA to be packaged into nascent viruses. The murine leukemia virus (MLV) is among the first retroviruses discovered and is classified as simple Retroviridae due to its minimal encoding capacity. The oncogenic and transduction abilities of MLV are extensively studied, whereas surprisingly the crucial step of its nuclear export has remained unsolved until 2014. Recent work has revealed the recruitment by MLV of the cellular NXF1/Tap-dependent pathway for export. Unconventionally, MLV uses of Tap to export both spliced and unspliced viral RNAs. Unlike other retroviruses, MLV does not harbor a unique RNA signal for export. Indeed, multiple sequences throughout the MLV genome appear to promote export of the unspliced MLV RNA. We review here the current understanding of the export mechanism and highlight the determinants that influence MLV export. As the molecular mechanism of MLV export is elucidated, we will gain insight into the contribution of the export pathway to the cytoplasmic fate of the viral RNA.

Keywords: MLV; NXF1/Tap; RNA export; cis-acting RNA element; gammaretrovirus; intron retention; intron-containing RNA; nucleocytoplasmic trafficking; post-transcriptional gene regulation; virus replication.

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Figures

Figure 1.
Figure 1.
The MLV genome and subgenomic SD’ and Env mRNAs. The primary transcript (8.3 kb RNA), named FL RNAGag-Pol, includes the 3 major genes: gag gene components, including the matrix (MA), p12, capsid (CA), and nucleocapsid (NC), the pol gene components, including the protease (PR), reverse transcriptase (RT) and integrase (IN) as well as the env sequence, coding for the surface (SU) and transmembrane (TM) components of viral envelope glycoprotein. A subset of this FL RNA goes through splicing and generates the SD' RNAp50 (4.4Kb) that derives from an alternative donor site (SD') within CA to the canonical splice acceptor site (SA) and codes for the p50 protein. A second fully-spliced RNA is generated, SD RNAEnv (3Kb) by splicing between the donor site (SD at position 205) and the acceptor site (SA at position 5490) encoding Env proteins.
Figure 2.
Figure 2.
MLV FL RNA is exported from the nucleus by Tap. (A) Export of cellular mRNA via Tap-dependent pathway. The major mRNA export factor Tap, coupled to its heterodimeric partner, p15, is required for formation of an export-competent mRNP including the major adaptors: the TREX/THO complex and the SRp20 protein recruited cotranscriptionally. For simplicity, not all adaptors have been depicted. The factors shared with the MLV RNA export are in red. (B) In contrast with MPMV FL RNA, the interaction between MLV FL RNA and Tap seems indirect and requires the intervention of cellular co-factors (blue pathway). Some subunits from the TREX complex (THOC7, THOC5 and UAP56) and SRp20 proteins (in red) have been identified to promote this interaction. In contrast, only UAP56 has been reported to be involved in export of MLV spliced SD RNA (green pathway). The crosses indicate the dispensable factors for viral RNA export. The question mark indicates that SRp20 contribution to the spliced viral RNA export has not been analyzed yet.
Figure 3.
Figure 3.
cis-acting motifs on MLV genome. Different sequences throughout the Mo-MLV RNA have been reported to be involved in FL RNA export. From 5′ to 3′: The RSL (R stem-loop), a signal made of 28nt folding in one stem-loop as pictured in (A); the Psi encapsidation signal which folds in 4 stem-loops (B); PTE which covers a large region in pol gene and contains 7 stem-loops with the first and seventh motif (SL1 & SL7 depicted in C) of special importance; the γ-CTE (D) within the PTE region harbors a short sequence AAGACA (in red) also found in the MPMV CTE and CAE which folds in 3 stem-loops (E), contains a 9nt core sequence (in red) necessary but not sufficient for the function of this motif. At the 3′ end the U3 region is required for the specific export of unspliced RNA however no precise motif has been highlighted in this region yet.
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