Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus

ABSTRACT The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these process...

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Autores principales:	Kun Zhang, Yucheng Zhang, Yunash Maharjan, Febri Gunawan Sugiokto, Jun Wan, Renfeng Li
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	reactivation lytic replication restriction factor m6A RNA modification YTHDF2 METTL3 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ff21e2c3aab344bc92c88a9fbea986fc
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spelling	oai:doaj.org-article:ff21e2c3aab344bc92c88a9fbea986fc2021-11-10T18:37:52ZCaspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus10.1128/mBio.01706-212150-7511https://doaj.org/article/ff21e2c3aab344bc92c88a9fbea986fc2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01706-21https://doaj.org/toc/2150-7511ABSTRACT The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Our study establishes that caspase disarming of the m6A RNA modification machinery fosters EBV replication. IMPORTANCE The discovery of an N6-methyladenosine (m6A) RNA modification pathway has fundamentally altered our understanding of the central dogma of molecular biology. This pathway is controlled by methyltransferases (writers), demethylases (erasers), and specific m6A binding proteins (readers). Emerging studies have linked the m6A RNA modification pathway to the life cycle of various viruses. However, very little is known regarding how this pathway is subverted to benefit viral replication. In this study, we established an unexpected linkage between cellular caspases and the m6A modification pathway, which is critical to drive the reactivation of a common tumor virus, Epstein-Barr virus (EBV).Kun ZhangYucheng ZhangYunash MaharjanFebri Gunawan SugioktoJun WanRenfeng LiAmerican Society for Microbiologyarticlereactivationlytic replicationrestriction factorm6A RNA modificationYTHDF2METTL3MicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	reactivation lytic replication restriction factor m6A RNA modification YTHDF2 METTL3 Microbiology QR1-502
spellingShingle	reactivation lytic replication restriction factor m6A RNA modification YTHDF2 METTL3 Microbiology QR1-502 Kun Zhang Yucheng Zhang Yunash Maharjan Febri Gunawan Sugiokto Jun Wan Renfeng Li Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
description	ABSTRACT The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Our study establishes that caspase disarming of the m6A RNA modification machinery fosters EBV replication. IMPORTANCE The discovery of an N6-methyladenosine (m6A) RNA modification pathway has fundamentally altered our understanding of the central dogma of molecular biology. This pathway is controlled by methyltransferases (writers), demethylases (erasers), and specific m6A binding proteins (readers). Emerging studies have linked the m6A RNA modification pathway to the life cycle of various viruses. However, very little is known regarding how this pathway is subverted to benefit viral replication. In this study, we established an unexpected linkage between cellular caspases and the m6A modification pathway, which is critical to drive the reactivation of a common tumor virus, Epstein-Barr virus (EBV).
format	article
author	Kun Zhang Yucheng Zhang Yunash Maharjan Febri Gunawan Sugiokto Jun Wan Renfeng Li
author_facet	Kun Zhang Yucheng Zhang Yunash Maharjan Febri Gunawan Sugiokto Jun Wan Renfeng Li
author_sort	Kun Zhang
title	Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
title_short	Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
title_full	Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
title_fullStr	Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
title_full_unstemmed	Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus
title_sort	caspases switch off the m<sup>6</sup>a rna modification pathway to foster the replication of a ubiquitous human tumor virus
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/ff21e2c3aab344bc92c88a9fbea986fc
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_version_	1718439835619819520

Caspases Switch off the m<sup>6</sup>A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus

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