A Poxvirus Decapping Enzyme Colocalizes with Mitochondria To Regulate RNA Metabolism and Translation and Promote Viral Replication

Cao, Shuai; Molina, Joshua A.; Cantu, Fernando; Hernandez, Candy; Yang, Zhilong

doi:10.1128/mbio.00300-22

Cited by 9 publications

(16 citation statements)

References 61 publications

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“…20,21,24,34,35 D9 has been found to be nonessential for viral replication in cultured cells, but deletion of D10 results in smaller plaque size and a reduction in replication. 23 This correlates with our observation of early gene expression having little effect on inducing host shutoff, (Figure 3) as D9 is an early viral gene and D10 is an intermediate gene expressed post-DNA replication where we see greater host shutoff. 20,45,46 This would suggest that the post-replicative gene D10 plays a more critical role than D9 to induce host shutoff.…”

Section: Vacv With Inactive/deleted Decapping Enzymes Retains the Abi...supporting

confidence: 88%

“…VACV‐encoded decapping enzymes (D9 and D10) that cause accelerated mRNA degradation are the most well‐studied VACV host shutoff factors 20,21,24,34,35 . D9 has been found to be nonessential for viral replication in cultured cells, but deletion of D10 results in smaller plaque size and a reduction in replication 23 . This correlates with our observation of early gene expression having little effect on inducing host shutoff, (Figure 3) as D9 is an early viral gene and D10 is an intermediate gene expressed post‐DNA replication where we see greater host shutoff 20,45,46 .…”

Section: Resultsmentioning

confidence: 99%

“…1 Particularly, two decapping enzymes, D9 and D10, that remove mRNA 5′cap and induce mRNA degradation, are believed to be significant contributors to VACV-induced host shutoff. [20][21][22][23][24] These studies do not exclude other major host shutoff factors encoded by VACV remaining to be identified.…”

mentioning

confidence: 95%

“…Multiple ways by which VACV induces host shutoff have been identified, including transcriptional inhibition, mRNA export, mRNA stability, and translation, as well as posttranslational protein degradation 1 . Particularly, two decapping enzymes, D9 and D10, that remove mRNA 5′cap and induce mRNA degradation, are believed to be significant contributors to VACV‐induced host shutoff 20–24 . These studies do not exclude other major host shutoff factors encoded by VACV remaining to be identified.…”

Section: Introductionmentioning

confidence: 99%

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Rapid and quantitative evaluation of vaccinia virus‐induced host shutoff using newly generated cell lines stably expressing secreted Gaussia luciferase

Molina

Yang

2022

Journal of Medical Virology

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Host shutoff, characterized by a global decline of cellular protein synthesis, is commonly observed in many viral infections, including vaccinia virus (VACV). Classic methods measuring host shutoff include the use of radioactive or nonradioactive probes to label newly synthesized proteins followed by radioautography or sodium dodecyl-sulfate polyacrylamide gel electrophoresis to resolve the proteins for follow-up detection. Although these are highly reliable methods, they are time-and labor-consuming. Here, we generated two cell lines stably expressing secreted Gaussia luciferase. These reporter cells allow rapid, quantitative, and consecutive monitoring of host shutoff from a single infection sample. We evaluated host shutoff induced by wild-type and various mutant VACVs using the reporter cell lines. The results validated the utilities of the reporter cells and quantitatively characterized VACV-induced host shutoff at different stages of replication. Notably, the results also indicated additional major unidentified VACV shutoff factors. Our study provides new tools to study host shutoff. The reporter cells are also suitable for high throughput settings and rapid testing of clinically isolated viruses. In combination with classical methods, these tools will greatly facilitate understanding of virusinduced host shutoff, and protein synthesis shutoff caused by other physiologically relevant stresses.

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Section: Vacv With Inactive/deleted Decapping Enzymes Retains the Abi...supporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Rapid and quantitative evaluation of vaccinia virus‐induced host shutoff using newly generated cell lines stably expressing secreted Gaussia luciferase

Molina

Yang

2022

Journal of Medical Virology

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“…Since that initial study, the VACV decapping enzymes D9 and D10 have each been shown to inhibit both PKR and RNase L activity. These enzymes act in concert with the host exoribonuclease Xrn1 to deplete both host and viral RNA, thereby reducing total intracellular dsRNA 22,[46][47][48] . However, as with rhtrs1, we did not detect any mutations in either of these VACV genes.…”

Section: Discussionmentioning

confidence: 99%

Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways

Banerjee

Smith

Geballe

et al. 2022

Preprint

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Cross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric vaccinia virus expressing the rhesus cytomegalovirus-derived PKR antagonist RhTRS1 in place of its native PKR antagonists; E3L and K3L (VACVΔEΔK+RhTRS1). Using this virus, we demonstrated that gene amplification of rhtrs1 occurred early during experimental evolution and was sufficient to fully rescue virus replication in partially resistant African green monkey (AGM) fibroblasts. Notably, this rapid gene amplification also allowed limited virus replication in otherwise completely non-permissive human fibroblasts, suggesting that gene amplification may act as a “molecular foothold” to facilitate viral adaptation to multiple species. In this study, we demonstrate that there are multiple barriers to VACVΔEΔK+RhTRS1 replication in human cells, mediated by both PKR and RNase L. We experimentally evolved three AGM-adapted virus populations in human fibroblasts. Each population adapted to human cells bimodally, via an initial 10-fold increase in replication after only two passages followed by a second 10-fold increase in replication by passage nine. Using our Illumina-based pipeline, we observed a rapid loss of a pre-existing AGM-adaptive SNP in the viral RNA polymerase, even though this variant provided a partial replication benefit in human cells. In addition, we found 13 single-base substitutions and short indels which increased over time, including two SNPs unique to HFF adapted populations. Many of these changes were associated with components of the viral RNA polymerase, although no variant was shared between all three populations. Taken together, our results demonstrate that rhtrs1 amplification was sufficient to increase viral tropism after passage in an “intermediate species” and subsequently enabled the virus to adopt different, species-specific adaptive mechanisms to overcome distinct barriers to viral replication in AGM and human cells.

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A review of Mpox: Biological characteristics, epidemiology, clinical features, diagnosis, treatment, and prevention strategies

Jiang,

Xu,

Guan

et al. 2024

Exploration

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The outbreak of monkeypox virus (MPXV) was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO), and the zoonotic disease caused by viral infection was renamed as “Mpox” on November 28, 2022. Currently, there is no approved vaccine or specific antiviral treatment for Mpox, and a main preventive strategy against MPXV infection remains the smallpox vaccine. Although there was an emergency use authorization (EUA) of Brincidofovir and Tecovirimat for the clinical treatment of clade II Mpox, while Tecovirimat failed to reduce the duration of Mpox lesions among patients infected with clade I Mpox in the Democratic Republic of the Congo (DRC). Therefore, it is still an urgent need to develop an effective medication. This review aims to enhance the understanding of Mpox and contribute to its prevention and treatment strategies, it provides a systemic introduction of the biological and epidemiological characteristics of MPXV, the clinical feature and diagnosis of Mpox, as well as treatment and prevention strategies, which will improve the comprehension about MPXV and offer potential strategies for clinical treatment.

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A Poxvirus Decapping Enzyme Colocalizes with Mitochondria To Regulate RNA Metabolism and Translation and Promote Viral Replication

Abstract: Decapping enzymes comprise many members from various organisms, ranging from plants, animals, and viruses. The mechanisms regulating their functions vary and are still largely unknown.

Cited by 9 publications

References 61 publications

Rapid and quantitative evaluation of vaccinia virus‐induced host shutoff using newly generated cell lines stably expressing secreted Gaussia luciferase

Rapid and quantitative evaluation of vaccinia virus‐induced host shutoff using newly generated cell lines stably expressing secreted Gaussia luciferase

Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways

A review of Mpox: Biological characteristics, epidemiology, clinical features, diagnosis, treatment, and prevention strategies

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