Abstract
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain N6-methyladenosine (m6A), allowing the recruitment of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), an m6A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries.
Highlights
Eukaryotic cells employ quality control mechanisms to ensure that each step of mRNA metabolism, from transcription to translation and decay, is properly executed in space and time and the genetic code is correctly expressed. mRNA surveillance and decay pathways are responsible for recognizing aberrant mRNAs that arise due to errors in the DNA template or by misprocesses occurring during mRNA biogenesis [1]
This cellular response usually involves the shut-off of protein synthesis and the concomitant assembly of RNA granules such as stress granules (SGs), which correspond to sites of mRNA triage and processing bodies (PBs), which contain the mRNA degradation machinery [15]
The human immunodeficiency virus type-1 (HIV-1) unspliced mRNA plays critical roles during viral replication since it is used (i) as the precursor mRNA molecule undergoing alternative splicing in order to generate the remaining viral transcripts; (ii) as the mRNA template for GAG and GAG–POL synthesis; and (iii) as the genome packaged into newly assembled viral particles
Summary
Eukaryotic cells employ quality control mechanisms to ensure that each step of mRNA metabolism, from transcription to translation and decay, is properly executed in space and time and the genetic code is correctly expressed. mRNA surveillance and decay pathways are responsible for recognizing aberrant mRNAs that arise due to errors in the DNA template or by misprocesses occurring during mRNA biogenesis [1]. In addition to CRM1, a large number of cellular proteins have been shown to influence REV’s functions in the nuclear export of unspliced and partially spliced viral mRNAs [36] These host factors include Matrin 3, host nuclear matrix protein (MATR3), an important host factor required to stabilize the viral RNA through its interaction with REV/RRE [37], REV-interacting protein (RIP)–REV/Rex activation domain-binding protein (RAB) [38,39], eukaryotic translation initiation factor 5A (eIF5A), Src-associated substrate in mitosis of 68 kDa (Sam68), and RNA helicases such as DEAD (Asp-Glu-Ala-Asp) box 3 (DDX3) [40], DDX1 [41], and RNA helicase A (RHA) [42], amongst others. It is still unclear what molecular mechanisms are in play and further investigation is needed to better understand this regulation
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