NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction

Wang, Jianshu; Chen, Jiyun; Wu, Guifen; Zhang, Hongling; Du, Xian; Chen, Suli; Zhang, Li; Wang, Ke; Fan, Jing; Gao, Shuaixin; Wu, Xudong; Zhang, Shouxiang; Kuai, Bin; Zhao, Peng; Chi, Binkai; Wang, Lantian; Li, Guohui; Wong, Catherine C. L.; Zhou, Yu; Li, Jinsong; Yun, Cai‐Hong; Cheng, Hong

doi:10.1101/gad.322602.118

Cited by 37 publications

(53 citation statements)

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“…To determine how late transcripts avoid degradation at their proper time of expression, we centered our attention on the human n uclear R NAi- de fective 2 (NRDE2) protein. NRDE2 localizes to nuclear speckles where it forms a 1:1 complex with MTR4 to inhibit its recruitment and RNA degradation (54). Given this protective activity, we hypothesized that KSHV uses NRDE2 to protect late transcripts from degradation.…”

Section: Resultsmentioning

confidence: 99%

“…Our data show that the host factor NRDE2 is required for evasion of PPD during late infection (Fig 5). NRDE2 function is linked to its residence in nuclear speckles, where it interacts with MTR4 to inhibit its activity thereby protecting speckle-associated mRNAs (54). As expression of KSHV late genes occurs at the onset of viral genome replication, we speculate that NRDE2 re-localizes to replication compartments (Fig 6B).…”

Section: Discussionmentioning

confidence: 99%

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Kaposi’s sarcoma-associated herpesvirus fine-tunes the temporal expression of late genes by manipulating a host RNA quality control pathway

Ruiz

Devlin

Kim

et al. 2020

Preprint

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AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncogenic nuclear DNA virus that expresses its genes using the host cell transcription and RNA processing machinery. As a result, KSHV transcripts are subject to degradation by at least two host-mediated nuclear RNA decay pathways, PABPN1 and PAPα/γ-mediated RNA decay (PPD) and an ARS2-dependent decay pathway. Here, we present global analyses of viral transcript levels to further understand the roles of these decay pathways in KSHV gene expression. Consistent with our recent report that the KSHV ORF57 protein increases viral transcript stability by impeding ARS2-dependent decay, ARS2 knockdown has little effect on viral gene expression 24 hours after lytic reactivation of wild-type virus. In contrast, inactivation of PPD results in premature accumulation of late transcripts. The up-regulation of late transcripts does not require the primary late gene-specific viral transactivation factor, suggesting that cryptic transcription produces the transcripts that then succumb to PPD. Remarkably, PPD inactivation has no effect on late transcripts at their proper time of expression. We show that this time-dependent PPD evasion by late transcripts requires the host factor NRDE2, which has previously been reported to protect cellular RNAs by sequestering decay factors. From these studies, we conclude that KSHV uses PPD to fine-tune the temporal expression of its genes by preventing their premature accumulation.ImportanceKaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that causes Kaposi’s sarcoma and other lymphoproliferative disorders. Nuclear expression of KSHV genes results in exposure to at least two host-mediated nuclear RNA decay pathways, PABPN1 and PAPα/γ-mediated RNA decay (PPD) and an ARS2-mediated decay pathway. Perhaps unsurprisingly, we previously found that KSHV uses specific mechanisms to protect its transcripts from ARS2-mediated decay. In contrast, here we show that PPD is required to dampen the expression of viral late transcripts that are prematurely transcribed, presumably due to cryptic transcription early in infection. At the proper time for their expression, KSHV late transcripts evade PPD through the activity of the host factor NRDE2. We conclude that KSHV fine-tunes the temporal expression of its genes by modulating PPD activity. Thus, the virus both protects from and exploits the host nuclear RNA decay machinery for proper expression of its genes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus fine-tunes the temporal expression of late genes by manipulating a host RNA quality control pathway

Ruiz

Devlin

Kim

et al. 2020

Preprint

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“…This temporal regulation was linked to nuclear speckles and the host nuclear RNAi-defective 2 (NRDE2) protein. NRDE2 is a negative regulator of exosomes through the formation of complexes with MTR4, which leads to inhibition of exosome-mediated degradation [63]. During late replication, the viral replication compartment merges with nuclear speckles where NRDE2 resides, leading to the formation of NRDE2 interactions with MTR4, which prevents the assembly of the PPD-mediated exosome complex [55].…”

Section: Nuclear Decaymentioning

confidence: 99%

Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection

Macveigh-Fierro

Rodríguez

Miles

et al. 2020

Viruses

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Kaposi’s sarcoma-associated herpesvirus (KSHV) induces life-long infections and has evolved many ways to exert extensive control over its host’s transcriptional and post-transcriptional machinery to gain better access to resources and dampened immune sensing. The hallmark of this takeover is how KSHV reshapes RNA fate both to control expression of its own gene but also that of its host. From the nucleus to the cytoplasm, control of RNA expression, localization, and decay is a process that is carefully tuned by a multitude of factors and that can adapt or react to rapid changes in the environment. Intriguingly, it appears that KSHV has found ways to co-opt each of these pathways for its own benefit. Here we provide a comprehensive review of recent work in this area and in particular recent advances on the post-transcriptional modifications front. Overall, this review highlights the myriad of ways KSHV uses to control RNA fate and gathers novel insights gained from the past decade of research at the interface of RNA biology and the field of KSHV research.

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“…It has been proposed that mRNAs are shuttled through nuclear speckles for assembly into export‐ready mRNPs (Akef, Zhang, Masuda, & Palazzo, ; Dias, Dufu, Lei, & Reed, ; Mor et al, ). A recent report even suggested that to further outrun nuclear decay, exosome activity is inhibited in nuclear speckles through the negative regulation of MTR4 by the nuclear RNAi defective‐2 (NRDE2) protein (J. Wang, Chen, et al, ). That is, NRDE2 is not only enriched in nuclear speckles, but it also physically interacts with MTR4 to lock it in a 1:1 stoichiometry, which blocks key residues of MTR4 involved in its recruitment to capped RNAs via the CBCA as well as to the exosome (Figure ).…”

Section: Main Bodymentioning

confidence: 99%

“…That is, NRDE2 is not only enriched in nuclear speckles, but it also physically interacts with MTR4 to lock it in a 1:1 stoichiometry, which blocks key residues of MTR4 involved in its recruitment to capped RNAs via the CBCA as well as to the exosome (Figure ). This combinatorial inhibition is suggested to promote productive export of mRNAs by providing a decay‐free zone in nuclear speckles (J. Wang, Chen, et al, ).…”

Section: Main Bodymentioning

confidence: 99%

Nuclear sorting of RNA

Garland

Jensen

2019

WIREs RNA

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The majority of the mammalian genome is transcribed by RNA polymerase II, yielding a vast amount of noncoding RNA (ncRNA) in addition to the standard production of mRNA. The typical nuclear biogenesis of mRNA relies on the tightly controlled coupling of co‐ and post‐transcriptional processing events, which ultimately results in the export of transcripts into the cytoplasm. These processes are subject to surveillance by nuclear RNA decay pathways to prevent the export of aberrant, or otherwise “non‐optimal,” transcripts. However, unlike mRNA, many long ncRNAs are nuclear retained and those that maintain enduring functions must employ precautions to evade decay. Proper sorting and localization of RNA is therefore an essential activity in eukaryotic cells and the formation of ribonucleoprotein complexes during early stages of RNA synthesis is central to deciding such transcript fate. This review details our current understanding of the pathways and factors that direct RNAs towards a particular destiny and how transcripts combat the adverse conditions of the nucleus. This article is categorized under: RNA Export and Localization > Nuclear Export/Import RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction

Cited by 37 publications

References 50 publications

Kaposi’s sarcoma-associated herpesvirus fine-tunes the temporal expression of late genes by manipulating a host RNA quality control pathway

Kaposi’s sarcoma-associated herpesvirus fine-tunes the temporal expression of late genes by manipulating a host RNA quality control pathway

Stealing the Show: KSHV Hijacks Host RNA Regulatory Pathways to Promote Infection

Nuclear sorting of RNA

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