METTL3 depletion blocks vesicular stomatitis virus replication in pancreatic cancer cells through the establishment of an intrinsic antiviral state DOI Creative Commons

Cassandra Catacalos-Goad,

Joseph A. Hawkins, Quinton Krueger

et al.

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

ABSTRACT Vesicular stomatitis virus (VSV) is a promising oncolytic (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the role of methyltransferase-like 3 (METTL3), catalytic subunit cellular writer complex that responsible for N6-methyladenosine (m6A) RNA modification, as potential host factor VSV replication in PDAC cells. METTL3 was previously shown to be upregulated PDAC, where it promotes cancer cell proliferation, invasion, and chemoresistance. The impact on life cycles viruses varies depending both type. Additionally, plays positive non-PDAC cells via m6A modification RNAs, which attenuates innate antiviral responses. 10 human lines uncovered two distinct outcomes. depletion did not affect with defective signaling, suggesting directly involved replication. contrast, dramatically inhibited functional signaling. We show result due RIG-I-dependent induction virus-independent, intrinsic state METTL3-depleted This marked by type-III (but type I or II) interferon secretion constitutive overexpression sensors [RIG-I (DDX58), MDA5 (IFIH1), LGP2 (DHX58)], transactivators (STAT1, IRF7, IRF9), diverse subset effectors, MX1, OAS1/2/3, IFIT1/3. IMPORTANCE Pancreatic deadly extremely challenging disease, making essential develop new treatment options improve patient survival rates. One approach use replication-competent “oncolytic viruses” designed specifically target destroy while sparing healthy ones. To create effective therapies cancer, crucial identify factors influence successful infection these viruses. Here, demonstrate protein METTL3, promote resistance chemotherapy, most tested lines. induces chronic inhibits viral Our study important understanding improving virus-based therapies.

Language: Английский

N123I mutation in the ALV-J receptor-binding domain region enhances viral replication ability by increasing the binding affinity with chNHE1 DOI Creative Commons
Mengmeng Yu, Yao Zhang, Li Zhang

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(2), P. e1011928 - e1011928

Published: Feb. 7, 2024

The subgroup J avian leukosis virus (ALV-J), a retrovirus, uses its gp85 protein to bind the receptor, chicken sodium hydrogen exchanger isoform 1 (chNHE1), facilitating viral invasion. ALV-J is main epidemic and shows noteworthy mutations within receptor-binding domain (RBD) region of gp85, especially in layer strains China. However, implications these on replication transmission remain elusive. In this study, strain JL08CH3-1 exhibited more robust ability than prototype HPRS103, which related variations protein. Notably, demonstrated heightened binding capacity chNHE1 compared HPRS103-gp85 binding. Furthermore, we showed that specific N123I mutation contributed enhanced chNHE1. Structural analysis indicated primarily stability expanded interaction interface, increased number bonds at interface increase between We found not only improved but also promoted shedding vivo . These comprehensive data underscore notion increases receptor intensifies replication.

Language: Английский

Citations

7
Post-Transcriptional Regulation of Viral RNA through Epitranscriptional Modification DOI Creative Commons
David G. Courtney

Cells, Journal Year: 2021, Volume and Issue: 10(5), P. 1129 - 1129

Published: May 7, 2021

The field of mRNA modifications has been steadily growing in recent years as technologies have improved and the importance these residues became clear. However, a subfield also arisen, specifically focused on how affect viral RNA, with possibility that viruses can be used model to best determine role play cellular mRNAs. First, virologists most abundant internal modification, m6A, mapping this modification elucidating its effects RNA wide range DNA viruses. Next, less common including m5C, Nm ac4C were investigated found present RNA. It now appears is littered multitude modifications. In biological systems are under constant evolutionary pressure out compete both host well newly arising mutants, it poses an interesting question about what benefit provide seems evident, at least author, selected for. review, I discuss identified roles uncovered for regard replication. Finally, propose some avenues research may shed further light exact

Language: Английский

Citations

33
The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity DOI Creative Commons
Jie Tong,

Wuchao Zhang,

Yuran Chen

et al.

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 3, 2022

Posttranscriptional modifications have been implicated in regulation of nearly all biological aspects cellular RNAs, from stability, translation, splicing, nuclear export to localization. Chemical also revealed for virus derived RNAs several decades before, along with the potential their regulatory roles infection. Due dynamic changes RNA during infection, illustrating mechanisms epigenetic regulations remains a challenge. Nevertheless, many studies indicated that these marks may directly regulate infection through antiviral innate immune responses. The present review summarizes impacts important on viral including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2'-O-methylation (2'-O-Methyl), and few uncanonical nucleotides (A-to-I editing, pseudouridine), immunity relevant signaling pathways, while highlighting significance responses

Language: Английский

Citations

28
Virus-Mimicking Polymer Nanoparticles Targeting CD169+ Macrophages as Long-Acting Nanocarriers for Combination Antiretrovirals DOI
Behnaz Eshaghi,

Josiane Fofana,

Sarah B. Nodder

et al.

ACS Applied Materials & Interfaces, Journal Year: 2022, Volume and Issue: 14(2), P. 2488 - 2500

Published: Jan. 7, 2022

Monosialodihexosylganglioside (GM3)-presenting lipid-coated polymer nanoparticles (NPs) that recapitulate the sequestration of human immunodeficiency virus-1 (HIV-1) particles in CD169

Language: Английский

Citations

24
Exploring the impact of m6A modification on immune diseases: mechanisms and therapeutic implication DOI Creative Commons
Yutong Chen, Min Liu,

Miao Lu

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 12, 2024

N 6 -methyladenosine (m A) is a chemical modification of RNA and has become widely discussed topic among scientific researchers in recent years. It distributed various organisms, including eukaryotes bacteria. been found that m A composed writers, erasers readers involved biological functions such as splicing, transport translation RNA. The balance the human immune microenvironment important for health abnormalities. Increasing studies have affects development diseases inflammatory enteritis systemic lupus erythematosus (SLE) by participating homeostatic regulation vivo . In this manuscript, we introduce composition, function, its progression diseases, providing new targets directions treatment clinical practice.

Language: Английский

Citations

4
Epitranscriptomic m 5 C methylation of SARS-CoV-2 RNA regulates viral replication and the virulence of progeny viruses in the new infection DOI Creative Commons
Hongyun Wang, Jiangpeng Feng, Zhiying Fu

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(32)

Published: Aug. 7, 2024

While the significance of N6-methyladenosine (m

Language: Английский

Citations

4
Epitranscriptomic m 6 A modifications during reactivation of HIV-1 latency in CD4 + T cells DOI Creative Commons
Tarun Mishra, Stacia Phillips, Yutao Zhao

et al.

mBio, Journal Year: 2024, Volume and Issue: 15(11)

Published: Oct. 7, 2024

ABSTRACT Despite effective antiretroviral therapy reducing HIV-1 viral loads to undetectable levels, the presence of latently infected CD4 + T cells poses a major barrier cure. N 6 -methyladenosine (m A) modification and cellular RNA has functional role in regulating infection. m A can affect its stability, translation, splicing suppresses type-I interferon induction macrophages. However, function latency reactivation remains unknown. We used Jurkat cell line-derived model (J-Lat cells) investigate changes levels response reversal. observed significant increase total upon latent J-Lat cells. This was transient returned steady-state despite continued high gene expression reactivated compared control Upregulation occurred without protein writers or erasers that add remove A, respectively. Knockdown significantly reduced reactivation. Treatment with an writer inhibitor along reduction Furthermore, using A-specific sequencing, we identified RNAs are differentially A-modified during validates these results established primary latency. These show importance IMPORTANCE is important for innate immune responses significance To address this question, study, models latency, sequencing at single-base resolution, assays. demonstrate reversal leads increased modification, correlates dependent on catalytic activity methyltransferase enzyme. also genes reactivation, as well sites within RNA. Our novel findings point toward

Language: Английский

Citations

4
Single-base m6A epitranscriptomics reveals novel HIV-1 host interaction targets in primary CD4+ T cells DOI Creative Commons
Siyu Huang, Yutao Zhao, Stacia Phillips

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract N 6 -methyladenosine (m A) is the most prevalent cellular mRNA modification and plays a critical role in regulating RNA stability, localization, gene expression. m A vital modulating expression of viral genes during HIV-1 infection. infection increases levels many cell types, which facilitates replication infectivity target cells. However, function primary CD4 + T cells remains unclear. Here, we demonstrate that Jurkat promotes interaction between writer complex subunits methyltransferase-like 3 14 (METTL3/METTL14). Using single-base A-specific sequencing, identified several differentially A-modified mRNAs, including perilipin ( PLIN3 ), Interestingly, increased level by enhancing its but protein was decreased. Knocking down reduced production enhanced virion infectivity. In contrast, cells, were unaffected infection, knocking out did not impact or These results indicate interplay cell-type specific only observed Overall, our highlight importance HIV-1-infected suggest significance as regulatory mechanism Author Summary common chemical on helps control important for this study, found two proteins, METTL3 METTL14, are responsible adding modifications to RNA. mRNAs with altered one called . stabilized levels, When knocked it decreased made particles more infectious. line, affect knockout alter infectivity, suggesting effect Our findings show host like unique infected

Language: Английский

Citations

0
The role of genetic diversity, epigenetic regulation, and sex-based differences in HIV cure research: a comprehensive review DOI Creative Commons

Punitha Letchumanan,

Kumitaa Theva Das

Epigenetics & Chromatin, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 3, 2025

Language: Английский

Citations

0
M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms DOI Creative Commons

Miaochun Fang,

Liwen Ye,

Yue Zhu

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 157 - 157

Published: Jan. 21, 2025

N6-methyladenosine (m6A) is the most abundant, dynamically reversible, and evolutionarily conserved internal chemical modification in eukaryotic RNA. It emerging as critical for regulating gene expression at post-transcriptional level by affecting RNA metabolism through, example, pre-mRNA processing, mRNA decay, translation. ALKBH5 has recently been identified an endogenous m6A demethylase implicated a multitude of biological processes. This review provides overview structural functional characteristics involvement diverse human diseases, including metabolic, immune, reproductive, nervous system disorders, well development inhibitors. In summation, this highlights current understanding structure, functions, detailed mechanisms various physiological pathological processes valuable insights clinical applications foundational research within related fields.

Language: Английский

Citations

0