The Complex Relationship between HTLV-1 and Nonsense-Mediated mRNA Decay (NMD)

Prochasson, Léa; Jalinot, Pierre; Mocquet, Vincent

doi:10.3390/pathogens9040287

Cited by 9 publications

(9 citation statements)

References 130 publications

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“…Co-IP experiments against Tax from HTLV-1-infected cells, identified INT6 (one of the thirteen eIF3 subunits) and UPF1 as interaction partners [ 156 ]. NMD inhibition by Tax depends on its interaction with INT6, as Tax mutants that are unable to bind to INT6 were found to have no effect on NMD [ 157 , 158 ], suggesting an involvement of eIF3 in NMD of mRNAs with long 3′-UTRs. In addition, Tax interacts with the helicase domain of UPF1 and reduces its RNA-binding affinity by blocking the RNA entry site.…”

Section: Viral Evasion Of Nmdmentioning

confidence: 99%

“…In addition, Tax interacts with the helicase domain of UPF1 and reduces its RNA-binding affinity by blocking the RNA entry site. Using single-molecule techniques, Tax was also shown to interact with RNA-bound UPF1, blocking its ATPase and helicase activities leading to the dissociation of UPF1 from the mRNA [ 156 , 158 ]. Taken together, Tax appears to inhibit NMD by binding UPF1 and INT6 and interfering with their interaction [ 156 ].…”

Section: Viral Evasion Of Nmdmentioning

confidence: 99%

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No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

Mailliot

Vega

Schaffitzel

2022

Biochemical Journal

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Nonsense-mediated messenger RNA decay (NMD) represents one of the main surveillance pathways used by eukaryotic cells to control the quality and abundance of mRNAs and to degrade viral RNA. NMD recognises mRNAs with a premature termination codon (PTC) and targets them to decay. Markers for a mRNA with a PTC, and thus NMD, are a long a 3′-untranslated region and the presence of an exon-junction complex (EJC) downstream of the stop codon. Here, we review our structural understanding of mammalian NMD factors and their functional interplay leading to a branched network of different interconnected but specialised mRNA decay pathways. We discuss recent insights into the potential impact of EJC composition on NMD pathway choice. We highlight the coexistence and function of different isoforms of up-frameshift protein 1 (UPF1) with an emphasis of their role at the endoplasmic reticulum and during stress, and the role of the paralogs UPF3B and UPF3A, underscoring that gene regulation by mammalian NMD is tightly controlled and context-dependent being conditional on developmental stage, tissue and cell types.

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Section: Viral Evasion Of Nmdmentioning

confidence: 99%

Section: Viral Evasion Of Nmdmentioning

confidence: 99%

No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

Mailliot

Vega

Schaffitzel

2022

Biochemical Journal

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“…Unspliced HTLV-1 mRNA, like the unspliced mRNA of other single-stranded positive-sense RNA members of the Retroviridae family, harbors an unusually long (~4-kilobase) 3'UTR that likely causes its observed targeting by NMD (Prochasson et al 2020). To counteract NMD, HTLV-1 has taken minimally a two-pronged approach by producing the trans-acting factors Rex and Tax.…”

Section: Viral-escape Strategies In Trans: Nmd Inhibitionmentioning

confidence: 99%

Viral subversion of nonsense-mediated mRNA decay

Popp

Cho²,

Maquat³

2020

RNA

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Viruses have evolved in tandem with the organisms that they infect. Afflictions of the plant and animal kingdoms with viral infections have forced the host organism to evolve new or exploit existing systems to develop the countermeasures needed to offset viral insults. As one example, nonsense-mediated mRNA decay, a cellular quality-control mechanism ensuring the translational fidelity of mRNA transcripts, has been used to restrict virus replication in both plants and animals. In response, viruses have developed a slew of means to disrupt or become insensitive to NMD, providing researchers with potential new reagents that can be used to more fully understand NMD mechanism. NONSENSE-MEDIATED mRNA DECAY IN PLANTS AND ANIMALS: AN OVERVIEWThe replication of genes during cell division, as well as gene expression (i.e. the synthesis of precursor-mRNAs, or pre-mRNAs, and the subsequent processing of pre-mRNAs to mRNAs), routinely results in low albeit detectable levels of mutations that can be deleterious. Before these mutations are etched into what is often the final effector of gene function, namely protein, it behooves the organism to eliminate them. As such, the cell has put in place quality-control systems to inspect and eliminate mRNAs that could affect fitness (Wolin and Maquat 2019). Nonsense-mediated mRNA decay (NMD) is one such Cold Spring Harbor Laboratory Press on May 4, 2021 -Published by rnajournal.cshlp.org Downloaded fromsystem. NMD eliminates transcripts that harbor a premature termination codon (PTC) and thereby could give rise to a truncated, non-functional or even toxic protein.In mammalian cells, NMD involves proteins coordinately attaching to, remodeling, and moving on RNAs. The machinery necessary for recognition of some NMD substrates is deposited during the process of gene transcription within nuclei, as reviewed extensively by Kurosaki and co-workers (Kurosaki et al. 2019) (Fig 1). For genes producing pre-mRNAs that undergo splicing, the act of splicing deposits a set of factors termed the exon-junction complex (EJC) at sites ~2024-nucleotides upstream of exonexon junctions, marking these locations. The nuclear EJC, composed of eukaryotic initiation factor 4A3 (eIF4A3), which is a helicase that anchors the EJC to the RNA, RNA-binding protein 8A (RBM8A; the mammalian homologue of Y14) and the protein mago nashi homolog (MAGOH), is further decorated with accessory factors and is maintained on spliced mRNAs during their export to the cytoplasm. There, mRNAs are initially translated while in complex with the capbinding complex (CBC), composed of cap-binding protein 80 (CBP80) and CBP20. Most termination codons are normally located in the final exon of mRNAs. However, should a ribosome terminate >5055-nucleotides upstream of an exonexon junction whose generation by splicing resulted in the deposition of an EJC, the ribosome will be unable to physically remove that EJC. Such termination events, which often occur at a PTC, allow eukaryotic release factor 1 (eRF1) and eRF3 to recruit the central NM...

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“…It has also been reported that Tax inhibits NMD via interaction with Upf1 and eIF3E/INT6 [33,34]. Recently, Prochasson et al elegantly reviewed the relationship between HTLV-1 and host NMD [35]. However, the offense and defense between HTLV-1 and NMD are complex and it remains unclear how HTLV-1 evades this powerful host mRNA quality control mechanism.…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the Mechanism of Host NMD Suppression by HTLV-1 Rex: Dissection of Rex to Identify the NMD Inhibitory Domain

Nakano

Karasawa

Hashizume

et al. 2022

Viruses

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The human retrovirus human T-cell leukemia virus type I (HTLV-1) infects human T cells by vertical transmission from mother to child through breast milk or horizontal transmission through blood transfusion or sexual contact. Approximately 5% of infected individuals develop adult T-cell leukemia/lymphoma (ATL) with a poor prognosis, while 95% of infected individuals remain asymptomatic for the rest of their lives, during which time the infected cells maintain a stable immortalized latent state in the body. It is not known why such a long latent state is maintained. We hypothesize that the role of functional proteins of HTLV-1 during early infection influences the phenotype of infected cells in latency. In eukaryotic cells, a mRNA quality control mechanism called nonsense-mediated mRNA decay (NMD) functions not only to eliminate abnormal mRNAs with nonsense codons but also to target virus-derived RNAs. We have reported that HTLV-1 genomic RNA is a potential target of NMD, and that Rex suppresses NMD and stabilizes viral RNA against it. In this study, we aimed to elucidate the molecular mechanism of NMD suppression by Rex using various Rex mutant proteins. We found that region X (aa20–57) of Rex, the function of which has not been clarified, is required for NMD repression. We showed that Rex binds to Upf1, which is the host key regulator to detect abnormal mRNA and initiate NMD, through this region. Rex also interacts with SMG5 and SMG7, which play essential roles for the completion of the NMD pathway. Moreover, Rex selectively binds to Upf3B, which is involved in the normal NMD complex, and replaces it with a less active form, Upf3A, to reduce NMD activity. These results revealed that Rex invades the NMD cascade from its initiation to completion and suppresses host NMD activity to protect the viral genomic mRNA.

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The Complex Relationship between HTLV-1 and Nonsense-Mediated mRNA Decay (NMD)

Cited by 9 publications

References 130 publications

No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

No-nonsense: insights into the functional interplay of nonsense-mediated mRNA decay factors

Viral subversion of nonsense-mediated mRNA decay

Elucidation of the Mechanism of Host NMD Suppression by HTLV-1 Rex: Dissection of Rex to Identify the NMD Inhibitory Domain

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