HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition

Fiorini, Francesca; Robin, Jean-Philippe; Kanaan, Joanne; Borowiak, Malgorzata; Croquette, Vincent; Hir, Hervé Le; Jalinot, Pierre; Mocquet, Vincent

doi:10.1038/s41467-017-02793-6

Cited by 30 publications

(57 citation statements)

References 66 publications

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“…Viral proteins from HTLV-1, MHV, ZIKV, HCV, and CaMV confer NMD resistance by directly targeting NMD or RNA decay factors (e.g., UPF1 or the EJC) (15,16,25,29,30). However, evidence of viral proteins directly binding to viral (or nonviral) transcripts and conferring NMD resistance is limited.…”

Section: Discussionmentioning

confidence: 99%

“…Virus-encoded proteins have also been implicated in conferring protection to NMD-sensitive gRNAs, as well as host mRNAs, by interfering with critical factors in the NMD pathway. For example, the human T-cell lymphotropic virus type I (HTLV-1) Tax protein binds to the helicase domain of UPF1, reducing its ability to bind RNA and promote NMD (25). HTLV-1 Tax expression also alters the morphology of P-bodies, representing a major site of NMD decay (26).…”

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confidence: 99%

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The Multifunctional Long-Distance Movement Protein of Pea Enation Mosaic Virus 2 Protects Viral and Host Transcripts from Nonsense-Mediated Decay

May

Johnson

Ilyas

et al. 2020

mBio

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The nonsense-mediated decay (NMD) pathway presents a challenge for RNA viruses with termination codons that precede extended 3= untranslated regions (UTRs). The umbravirus Pea enation mosaic virus 2 (PEMV2) is a nonsegmented, positive-sense RNA virus with an unusually long 3= UTR that is susceptible to NMD. To establish a systemic infection, the PEMV2 long-distance movement protein p26 was previously shown to both stabilize viral RNAs and bind them for transport through the plant's vascular system. The current study demonstrated that p26 protects both viral and nonviral messenger RNAs from NMD. Although p26 localizes to both the cytoplasm and nucleolus, p26 exerts its anti-NMD effects exclusively in the cytoplasm independently of long-distance movement. Using a transcriptome-wide approach in the model plant Nicotiana benthamiana, p26 protected a subset of cellular NMD target transcripts, particularly those containing long, structured, GC-rich 3= UTRs. Furthermore, transcriptome sequencing (RNA-seq) revealed that the NMD pathway is highly dysfunctional during PEMV2 infection, with 1,820 (48%) of NMD targets increasing in abundance. Widespread changes in the host transcriptome are common during plant RNA virus infections, and these results suggest that, in at least some instances, virus-mediated NMD inhibition may be a major contributing factor. IMPORTANCE Nonsense-mediated decay (NMD) represents an RNA regulatory pathway that degrades both natural and faulty messenger RNAs with long 3= untranslated regions. NMD targets diverse families of RNA viruses, requiring that viruses counteract the NMD pathway for successful amplification in host cells. A protein required for long-distance movement of Pea enation mosaic virus 2 (PEMV2) is shown to also protect both viral and host mRNAs from NMD. RNA-seq analyses of the Nicotiana benthamiana transcriptome revealed that PEMV2 infection significantly impairs the host NMD pathway. RNA viruses routinely induce large-scale changes in host gene expression, and, like PEMV2, may use NMD inhibition to alter the host transcriptome in an effort to increase virus amplification.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Multifunctional Long-Distance Movement Protein of Pea Enation Mosaic Virus 2 Protects Viral and Host Transcripts from Nonsense-Mediated Decay

May

Johnson

Ilyas

et al. 2020

mBio

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“…NMD is triggered during translation of PTC-containing transcripts to prevent the production of potentially deleterious truncated proteins. However, NMD gets frequently inactivated globally; for example, by viral infections, the tumor microenvironment or upon endoplasmic reticulum stress [18][19][20][21][22] . Thus, fail-safe mechanisms must be in place for RBPs that regulate their levels through unproductive splicing.…”

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confidence: 99%

SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly

Königs

Machado

Arnold

et al. 2020

Nat Struct Mol Biol

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Results SRSF7 overexpression induces auto-regulation.To investigate the mechanisms of SRSF7 homeostasis, we generated cell lines SRSF7 is an essential RNA-binding protein whose misexpression promotes cancer. Here, we describe how SRSF7 maintains its protein homeostasis in murine P19 cells using an intricate negative feedback mechanism. SRSF7 binding to its premessenger RNA promotes inclusion of a poison cassette exon and transcript degradation via nonsense-mediated decay (NMD). However, elevated SRSF7 levels inhibit NMD and promote translation of two protein halves, termed Split-ORFs, from the bicistronic SRSF7-PCE transcript. The first half acts as dominant-negative isoform suppressing poison cassette exon inclusion and instead promoting the retention of flanking introns containing repeated SRSF7 binding sites. Massive SRSF7 binding to these sites and its oligomerization promote the assembly of large nuclear bodies, which sequester SRSF7 transcripts at their transcription site, preventing their export and restoring normal SRSF7 protein levels. We further show that hundreds of human and mouse NMD targets, especially RNA-binding proteins, encode potential Split-ORFs, some of which are expressed under specific cellular conditions. SRSF7 binding promotes splicing of NMD-sensitive and -resistant SRSF7 isoforms. To understand the mechanism of SRSF7 auto-regulation, we examined the binding of SRSF7 protein to SRSF7 transcripts using individual-nucleotide resolution ultraviolet (UV) crosslinking and immunoprecipitation (iCLIP). We used normalized significant crosslink events (X-links, false discovery rate (FDR) < 0.05) from SRSF3 and SRSF7 iCLIP datasets of P19 cell lines without OE 8 . Similar to SRSF3, which promotes the inclusion of the PCE in SRSF7 transcripts 17 , SRSF7 showed enriched crosslinks in an extended region encompassing the PCE, its flanking introns 3a and 3b, and exons 3, 4 and 5 ( Fig. 1d). Quantification revealed that SRSF7 binds ~50-fold more to SRSF7 transcripts than SRSF3 ( Supplementary Table 1), indicating that SRSF7 has an unusual preference for its own transcripts.RNA-seq followed by quantification of junction reads revealed that SRSF7 OE promotes inclusion of either the complete PCE (460 nucleotides (nt)) or a partial PCE (107 nt) in SRSF7 transcripts ( Fig. 1e). Additionally, both PCE-flanking introns (3a and 3b) and intron 5 displayed increased read coverage, indicating that they are partly retained upon SRSF7 OE. Semiquantitative reverse transcription PCR and sequencing confirmed that SRSF7 OE caused the appearance of transcripts containing the entire PCE (SRSF7-PCE, orange asterisk), the partial PCE (SRSF7-PCE 1/4 , yellow asterisk) or the PCE in combination with both flanking introns (SRSF7-I3a+b, red asterisk) or with only intron 3b (SRSF7-I3b, green asterisk; Fig. 1f and Extended Data Fig. 1b,c). Identical isoforms were detected for endogenous and SRSF7-GFP reporter transcripts, indicating that auto-regulation operates similarly on both.All these transcripts contain PTCs and should be s...

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“…In lung inflammatory myofibroblast tumours, decreased NMD leads to the increased expression of the transcript for the NIK protein kinase, which activates the NF-B pathway and promotes cytokine expression and inflammation [132]. Supporting this observation, the stabilization of the NIK mRNA half-life was observed in a separate Tax-and a Rexdependent manner [58,119]. Additionally, it is worth noting that NMD is involved in the apoptotic response induced by high stress levels; more precisely, it has been demonstrated that maintained NMD inhibition induces cell death [133,134].…”

Section: When Does Nmd Inhibition Occur During Htlv-1 Infection?mentioning

confidence: 86%

“…Second, when UPF1 is already bound to RNA (due to its action in NMD), Tax binding blocks ATP hydrolysis and helicase activity, freezing UPF1 on RNA. These observations suggest a broad effect on UPF1 with the capacity to impact NMD at different steps [119]. When analysing viral mRNA, it is difficult to dissociate the transactivation role of Tax on the viral promoter from its post-transcriptional effect via NMD.…”

Section: Htlv-1 Protection Against Nmdmentioning

confidence: 99%

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

Prochasson¹,

Jalinot²,

Mocquet³

2020

Preprint

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Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition.HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct longterm impact remains to be investigated.

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HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition

Cited by 30 publications

References 66 publications

The Multifunctional Long-Distance Movement Protein of Pea Enation Mosaic Virus 2 Protects Viral and Host Transcripts from Nonsense-Mediated Decay

The Multifunctional Long-Distance Movement Protein of Pea Enation Mosaic Virus 2 Protects Viral and Host Transcripts from Nonsense-Mediated Decay

SRSF7 maintains its homeostasis through the expression of Split-ORFs and nuclear body assembly

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

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