Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication

Zhang, Xueyan; Hao, Haojie; Ma, Li; Zhang, Yecheng; Hu, Xiao; Chen, Zhe; Liu, Di; Yuan, Jun; Hu, Zhangli; Guan, Wuxiang

doi:10.1128/mbio.01067-21

Cited by 66 publications

(61 citation statements)

References 72 publications

(86 reference statements)

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“…At the epigenetic level, arginine alters RNA methylation via methyltransferase like 14 (METTL14) interaction with N6-methyladenosine (m6A), a mechanism documented in COVID-19 pathogenesis ( Li et al., 2021 ; Zhang et al., 2021 ). Interestingly, a dysfunctional m6A methylome was recently reported in tauopathies, implicating RNA methylation in these disorders ( Jiang et al., 2021 ).…”

Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…These data were validated using the orthogonal meRIP-Seq methodology ( 61 , 110 ) and also served to show that inhibiting the enzymatic activity of METTL3 led to reduced titers of both SARS-CoV-2 and HCoV-OC43. The installation of m 6 A on a small number of SARS-CoV-2 sgRNAs was further validated by additional studies ( 111 , 112 ) using comparative DRS approaches allied with Tombo, MINES, and m6ANet. Another recent study utilized Tombo to show that the SARS-CoV-2 epitranscriptome remained stable during infection of Vero cells ( 113 ).…”

Section: Nanopore-mediated Detection Of Rna Modifications In Viral Co...mentioning

confidence: 95%

Nanopore-Based Detection of Viral RNA Modifications

Abebe

Verstraten

Depledge

2022

mBio

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“…Expression levels of the eraser FTO are reduced 48 hpi, while ALKBH5 is not affected. All these enzymes are normally present in the nucleus but colocalize in the cytoplasm when the cell is infected [22]. Finally, YTHDF members, such as YTHDF1-3, YTH domain containing (YTHDC) 1, and YTHDC2, do not change during the infection [22].…”

Section: Introductionmentioning

confidence: 99%

“…All these enzymes are normally present in the nucleus but colocalize in the cytoplasm when the cell is infected [22]. Finally, YTHDF members, such as YTHDF1-3, YTH domain containing (YTHDC) 1, and YTHDC2, do not change during the infection [22]. Liu et al demonstrated that an increase of viral replication occurred by knocking down METTL3, METTL14, and YTHDF2, while, on the contrary, when the ALKBH5 was knocked down, SARS-CoV-2 infection drastically decreased [23].…”

Section: Introductionmentioning

confidence: 99%

“…Liu et al demonstrated that an increase of viral replication occurred by knocking down METTL3, METTL14, and YTHDF2, while, on the contrary, when the ALKBH5 was knocked down, SARS-CoV-2 infection drastically decreased [23]. Additionally, other authors reported that depletion of METTL3 [22,24], YTHDF1, and YTHDF3 [24] affected SARS-CoV-2 and also the seasonal human β-coronavirus HCoV-OC43 replication by reducing viral RNAs and protein expression. Furthermore, Meng et al indicated that RBM15 was highly expressed in severe COVID-19 patients, and its knockdown was associated with decreased cell death and inflammatory response [25].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of m6A Methylation as a New Therapeutic Option against COVID-19

et al. 2021

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The rapid spread of SARS-CoV-2 and the resulting pandemic has led to a spasmodic search for approaches able to limit the diffusion of the disease. The epigenetic machinery has aroused considerable interest in the last decades, and much evidence has demonstrated that this type of modification could regulate the early stages of viral infection. Recently it was reported that N6-methyladenosine (m6A) influences SARS-CoV-2 replication, although its role remains to be further investigated. The knockdown of enzymes involved in the m6A pathway could represent an optimal strategy to deepen the epigenetic mechanism. In the present study, we blocked the catalytic activity of the fat mass and obesity-associated protein (FTO) by using the selective inhibitor rhein. We observed a strong broad-spectrum reduction of infectivity caused by various coronaviruses, including SARS-CoV-2. This effect could be due to the modulation of m6A levels and could allow identification of this modification as a new therapeutic target to treat SARS-CoV-2 infection.

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Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication

Cited by 66 publications

References 72 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Nanopore-Based Detection of Viral RNA Modifications

Regulation of m6A Methylation as a New Therapeutic Option against COVID-19

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