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

RNA modifications: importance in immune cell biology and related diseases DOI Creative Commons
Lian Cui, Rui Ma,

Jiangluyi Cai

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Language: Английский

Citations

200
RNA Modification in the Immune System DOI Creative Commons
Dali Han,

Meng Xu

Annual Review of Immunology, Journal Year: 2023, Volume and Issue: 41(1), P. 73 - 98

Published: April 26, 2023

Characterization of RNA modifications has identified their distribution features and molecular functions. Dynamic changes in modification on various forms are essential for the development function immune system. In this review, we discuss value innovative profiling technologies to uncover these diverse, dynamic cells within healthy diseased contexts. Further, explore our current understanding mechanisms whereby aberrant modulate milieu tumor microenvironment point out outstanding research questions.

Language: Английский

Citations

45
Physiological functions of RIG-I-like receptors DOI Creative Commons
Mitsutoshi Yoneyama, Hiroki Kato, Takashi Fujita

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 731 - 751

Published: April 1, 2024

Language: Английский

Citations

21
m6A modifications regulate intestinal immunity and rotavirus infection DOI Creative Commons
Anmin Wang,

Wanyiin Tao,

Jiyu Tong

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 31, 2022

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, the in vivo function of intestinal immune defense against infections largely unknown. Here, we uncover a novel antiviral rotavirus (RV) infection small bowel epithelial cells (IECs). We found that induced global modifications on transcripts by down-regulating m6a eraser ALKBH5. Mice lacking writer enzymes METTL3 IECs (Mettl3ΔIEC) were resistant to RV showed increased expression interferons (IFNs) IFN-stimulated genes (ISGs). Using RNA-sequencing RNA immuno-precipitation (RIP)-sequencing, identified IRF7, master regulator IFN responses, one primary targets infection. In absence METTL3, Irf7 stability enhanced type I III expression. Deficiency IRF7 attenuated elevated IFNs ISGs restored susceptibility Mettl3ΔIEC mice. Moreover, declined with age mice, significant drop from 2 weeks 3 post birth, which likely has broad implications for development system enteric viruses early life. Collectively, demonstrated host m6A-IRF7-IFN signaling cascade restricts vivo.

Language: Английский

Citations

39
Functional Impacts of Epitranscriptomic m6A Modification on HIV-1 Infection DOI Creative Commons
Stacia Phillips, Tarun Mishra, Siyu Huang

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(1), P. 127 - 127

Published: Jan. 16, 2024

Epitranscriptomic RNA modifications play a crucial role in the posttranscriptional regulation of gene expression. N6-methyladenosine (m6A) is most prevalent internal modification eukaryotic and plays pivotal fate. m6A regulated by group cellular proteins, methyltransferases (writers) demethylases (erasers), which add remove methyl from adenosine, respectively. recognized RNA-binding proteins (readers) that specifically bind to m6A-modified RNA, mediating effects on stability, splicing, transport, translation. The functional significance viral an active area virology research. In this review, we summarize analyze current literature HIV-1 multifaceted functions regulating replication, evading innate immune responses infection. Furthermore, briefly discuss future directions therapeutic implications mechanistic studies epitranscriptomic modifications.

Language: Английский

Citations

12
Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification DOI Creative Commons
Anastasiya Kostyusheva, Sergey Brezgin, Dieter Glebe

et al.

Emerging Microbes & Infections, Journal Year: 2021, Volume and Issue: 10(1), P. 2264 - 2275

Published: Jan. 1, 2021

Hepatitis B virus (HBV) is a DNA with complex life cycle that includes reverse transcription step. HBV poorly sensed by the immune system and frequently establishes persistent infection can cause chronic infection, leading of liver cancer cirrhosis worldwide. Recent mounting evidence has indicated growing importance RNA methylation (m6A modification) in viral replication, escape, carcinogenesis. The value m6A modification for prediction clinical management remains to be assessed. However, number studies indicate important role m6A-marked transcripts factors machinery managing HBV-related pathologies. In this review, we discuss fundamental potential impact modifications on pathogenesis, as well highlight molecular techniques tools used studying methylome.

Language: Английский

Citations

56
Regulation of antiviral innate immunity by chemical modification of viral RNA DOI Creative Commons
Na Li, Tariq M. Rana

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2022, Volume and Issue: 13(6)

Published: Feb. 12, 2022

Abstract More than 100 chemical modifications of RNA, termed the epitranscriptome, have been described, most which occur in prokaryotic and eukaryotic ribosomal, transfer, noncoding RNA messenger RNA. DNA viruses can modify their either directly via genome‐encoded enzymes or by hijacking host enzymatic machinery. Among many described to date, four play particularly important roles promoting viral infection facilitating gene expression replication enabling escape from innate immune response. Here, we discuss our current understanding mechanisms such as N 6 ‐methyladenosine (m6A), ,2′‐ O ‐dimethyladenosine (m6Am), 5‐methylcytidine (m5C), N4‐acetylcytidine (ac4C), 2′‐ ‐methylation (Nm) promote and/or suppress recognition sensors downstream activation antiviral This article is categorized under: Disease Development > Structure Dynamics Influence Biological Systems Evolution Genomics Ribonucleoprotein

Language: Английский

Citations

38
Milk exosomes elicit a potent anti-viral activity against dengue virus DOI Creative Commons
Vengala Rao Yenuganti, Sumbul Afroz, Rafiq Ahmad Khan

et al.

Journal of Nanobiotechnology, Journal Year: 2022, Volume and Issue: 20(1)

Published: July 6, 2022

Exosomes are nano-sized vesicles secreted by various cells into the intra and extracellular space hence is an integral part of biological fluids including milk. In last few decades, many research groups have proved potential milk exosomes as a sustainable, economical non-immunogenic drug delivery therapeutic agent against different pathological conditions. However, its anti-viral properties still remain to be unearthed.Here, we been able isolate, purify characterize derived from Cow (CME) Goat (GME) further studied antiviral Dengue virus (DENV), Newcastle Disease Virus strain Komarov (NDV-K) Human Immunodeficiency (HIV-1) using in-vitro infection system.TEM, NTA DLS analysis validated appropriate size isolated cow goat (30-150 nm). Real-time PCR immunoblotting results confirmed presence several exosomal miRNAs protein markers. Our findings suggest that GME significantly decreased infectivity DENV. addition, reduces DENV replication reduced secretion mature virions. Furthermore, heat inactivation did not show any inhibition on infection, replication, RNase treatment abrogates indicating direct role in inhibition. addition inhibited NDV-K, but HIV-1, suggesting mediated activity might specific.This study demonstrates opens new avenues for development exosome-based therapies treat viral diseases.

Language: Английский

Citations

30
m6A reader proteins: the executive factors in modulating viral replication and host immune response DOI Creative Commons
Decheng Yang, Guangze Zhao,

Huifang Mary Zhang

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: May 30, 2023

N 6 -Methyladenosine (m A) modification is the most abundant covalent of RNA. It a reversible and dynamic process induced by various cellular stresses including viral infection. Many m A methylations have been discovered, on genome RNA viruses transcripts DNA viruses, these play positive or negative role life cycle depending species. The machinery, writer, eraser, reader proteins, achieves its gene regulatory functioning in an orchestrated manner. Notably, data suggest that biological effects target mRNAs predominantly depend recognition binding different readers. These readers include, but are not limited to, YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoproteins (HNRNPs), insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), many others discovered recently. Indeed, recognized only as regulators metabolism also participants variety processes, although some reported roles still controversial. Here, we will summarize recent advances discovery, classification, functional characterization particularly focusing their mechanisms action metabolism, expression, replication. In addition, briefly discuss A-associated host immune responses

Language: Английский

Citations

17
Modifying the antiviral innate immune response by selective writing, erasing, and reading of m6A on viral and cellular RNA DOI Creative Commons

Caroline J. Aufgebauer,

Katherine M. Bland, Stacy M. Horner

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(1), P. 100 - 109

Published: Jan. 1, 2024

Language: Английский

Citations

7