Exploring New Functional Aspects of HTLV-1 RNA-Binding Protein Rex: How Does Rex Control Viral Replication?

Nakano, Kazumi; Yokoyama, Kôichi; Shin, Shuichi; Uchida, Koki; Tsuji, Kazuki; Tanaka, Marie; Uchimaru, Kaoru; Watanabe, Toshiki

doi:10.3390/v14020407

Cited by 6 publications

(5 citation statements)

References 50 publications

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“…With regards to this role, it is expected that CRM1 hijacking by Rex and Rev will lead to specific post-transcriptional deregulations due to NMD inhibition. Some of these deregulations have already been addressed 62 but a dedicated study is still needed to unravel the significance of these effects during viral infection.…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

Prochasson,

Mghezzi-Habellah,

Roisin

et al. 2023

Preprint

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The hijacking of CRM1 export is an important step of the retroviral replication cycle. Here, we investigated the consequences of this hijacking for the host. During HTLV-1 infection, we identified the formation of a complex composed of Rex, CRM1 and the RNA helicase UPF1, leading to the nuclear retention of UPF1. We further showed how this leads to the inhibition of the nonsense mediated mRNA decay (NMD), known to have an antiviral function. Corroborating these results, we described a similar process with Rev, the functional homolog of Rex from HIV-1. Unexpectedly, we also found that, for HTLV-1 , this process is coupled with the specific loading of UPF1 onto vRNA, independently of NMD. In this latter context, UPF1 positively regulates several steps of the viral replication cycle, from the nuclear export of vRNA to the production of mature viral particles.

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Section: Discussionmentioning

confidence: 99%

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

Prochasson,

Mghezzi-Habellah,

Roisin

et al. 2023

Preprint

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“…The role of Rex in HTLV-1 pathogenesis has been extensively reported already. Indeed, it is known for mediating the transport of unspliced or incompletely spliced viral structural proteins out of the nucleus to promote viral particle formation ( 118 , 119 ). Although its potential role in splicing modulation had not been tackled in the HTLV-1 infection context yet, few studies did look into it, but in the HTLV-2 framework.…”

Section: Rna Splicing In Htlv-1 Infectionmentioning

confidence: 99%

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

2022

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Eukaryotic cells employ a broad range of mechanisms to regulate gene expression. Among others, mRNA alternative splicing is a key process. It consists of introns removal from an immature mRNA (pre-mRNA) via a transesterification reaction to create a mature mRNA molecule. Large-scale genomic studies have shown that in the human genome, almost 95% of protein-encoding genes go through alternative splicing and produce transcripts with different exons combinations (and sometimes retained introns), thus increasing the proteome diversity. Considering the importance of RNA regulation in cellular proliferation, survival, and differentiation, alterations in the alternative splicing pathway have been linked to several human cancers, including adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive and fatal malignancy caused by the Human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes for two oncoproteins: Tax and HBZ, both playing significant roles in the transformation of infected cells and ATL onset. Here, we review current knowledge on alternative splicing and its link to cancers and reflect on how dysregulation of this pathway could participate in HTLV-1-induced cellular transformation and adult T-cell leukemia/lymphoma development.

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“…We speculate that Rex has as yet unknown aspects to escort viral RNAs from the transcription to the translation. To explore new aspects of Rex, we recently conducted transcriptome and interactome analysis of Rex (143). Firstly, we conducted the interactome analysis of Rex in HEK293T cells overexpressing His-Halo-tagged Rex.…”

Section: Reaffirming Rex As a Key Regulator Of Viral Gene Expressionmentioning

confidence: 99%

Tuning Rex rules HTLV-1 pathogenesis

Nakano

Watanabe

2022

Front. Immunol.

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HTLV-1 is an oncovirus causing ATL and other inflammatory diseases such as HAM/TSP and HU in about 5% of infected individuals. It is also known that HTLV-1-infected cells maintain a disease-free, immortalized, latent state throughout the lifetimes of about 95% of infected individuals. We believe that the stable maintenance of disease-free infected cells in the carrier is an intrinsic characteristic of HTLV-1 that has been acquired during its evolution in the human life cycle. We speculate that the pathogenesis of the virus is ruled by the orchestrated functions of viral proteins. In particular, the regulation of Rex, the conductor of viral replication rate, is expected to be closely related to the viral program in the early active viral replication followed by the stable latency in HTLV-1 infected T cells. HTLV-1 and HIV-1 belong to the family Retroviridae and share the same tropism, e.g., human CD4+ T cells. These viruses show significant similarities in the viral genomic structure and the molecular mechanism of the replication cycle. However, HTLV-1 and HIV-1 infected T cells show different phenotypes, especially in the level of virion production. We speculate that how the activity of HTLV-1 Rex and its counterpart HIV-1 Rev are regulated may be closely related to the properties of respective infected T cells. In this review, we compare various pathological aspects of HTLV-1 and HIV-1. In particular, we investigated the presence or absence of a virally encoded “regulatory valve” for HTLV-1 Rex or HIV-1 Rev to explore its importance in the regulation of viral particle production in infected T cells. Finally, wereaffirm Rex as the key conductor for viral replication and viral pathogenesis based on our recent study on the novel functional aspects of Rex. Since the activity of Rex is closely related to the viral replication rate, we hypothesize that the “regulatory valve” on the Rex activity may have been selectively evolved to achieve the “scenario” with early viral particle production and the subsequent long, stable deep latency in HTLV-1 infected cells.

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Exploring New Functional Aspects of HTLV-1 RNA-Binding Protein Rex: How Does Rex Control Viral Replication?

Cited by 6 publications

References 50 publications

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

Tuning Rex rules HTLV-1 pathogenesis

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