Targeting the RNA m6A modification for cancer immunotherapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: March 16, 2022

Abstract N 6 -methyladenosine (m A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription translation programs that promote cancer occurrence progression. Although defective gene regulation resulting from m A often affects oncogenic tumor-suppressing networks, can also modulate tumor immunogenicity immune cells involved in anti-tumor responses. Understanding this counterintuitive concept aid design new drugs target to potentially improve outcomes immunotherapies. Here, we provide an up-to-date comprehensive overview how modifications intrinsically affect alterations cell extrinsically responses microenvironment (TME). We review strategies for modulating endogenous immunity discuss challenge reshaping TME. Strategies include: combining specific efficient inhibitors against regulators with checkpoint blockers; generating effective programmable gene-editing system enables manipulation individual sites; establishing enhance T or natural killer cells; using nanoparticles specifically tumor-associated macrophages (TAMs) deliver messenger RNA small interfering A-related molecules repolarize TAMs, enabling them remodel The goal help field understand shape TME so better immunotherapy be designed developed.

Language: Английский

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RNA Modification in the Immune System

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

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Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: May 2, 2024

Abstract N6‐methyladenosine (m 6 A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role oral mucosal immunity remains ambiguous. Periodontitis a special but prevalent infectious disease characterized as hyperinflammation of mucosa bone resorption. Here, it reported that genetic deletion Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability TNFAIP3 (also known A20) transcript significantly attenuated upon m A modification. When silencing METTL3, accumulated functioning ubiquitin‐editing enzyme facilitates ubiquitination NEK7 [NIMA (never mitosis gene a)‐related kinase 7], subsequently impairs assembly. Furtherly, Coptisine chloride, natural small‐molecule, discovered novel METTL3 inhibitor performs therapeutic effect on periodontitis. The study unveils previously unknown pathogenic mechanism METTL3‐mediated modifications periodontitis indicates potential target.

Language: Английский

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m6A modifications regulate intestinal immunity and rotavirus infection

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

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Emerging role of METTL3 in inflammatory diseases: mechanisms and therapeutic applications

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 21, 2023

Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney and autoimmune diseases have high incidence rates, still threaten human health, represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis various diseases. As most widely discussed m6A methyltransferase, pathogenic role METTL3 has become research hotspot, but there been no comprehensive review topic. Here, we summarize expression changes, modified target genes, related cardiovascular, metabolic, degenerative, immune, infectious well tumors. In addition epithelial cells, endothelial fibroblasts, also regulates function inflammation-related immune including macrophages, neutrophils, dendritic Th17 NK cells. Regarding therapeutic applications, serves for treatment with natural plant drug components, emodin, cinnamaldehyde, total flavonoids Abelmoschus manihot , resveratrol. This focuses on recent advances initiation, development, application Knowledge specific regulatory mechanisms involving can help deepen understanding lay foundation development precisely targeted drugs address processes.

Language: Английский

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m6A reader proteins: the executive factors in modulating viral replication and host immune response

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

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

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

Published: Jan. 1, 2024

Language: Английский

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N6-methyladenosine modification—a key player in viral infection

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: Oct. 12, 2023

Abstract N 6 -methyladenosine (m A) modification is a dynamic, reversible process and the most prevalent internal of RNA. This regulated by three protein groups: methyltransferases (“writers”), demethylases (“erasers”), m A-binding proteins (“readers”). A related enzymes could represent an optimal strategy to deepen epigenetic mechanism. Numerous reports have suggested that aberrant modifications lead expression important viral genes. Here, we review role in replication virus–host interactions. In particular, focus on DNA RNA viruses associated with human diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immunodeficiency virus (HIV)-1, Epstein–Barr (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV). These findings will contribute understanding mechanisms interactions design future therapeutic targets for treatment tumors infections.

Language: Английский

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RNA m⁶A Methylation Suppresses Insect Juvenile Hormone Degradation to Minimize Fitness Costs in Response to A Pathogenic Attack

Advanced Science, Journal Year: 2023, Volume and Issue: 11(6)

Published: Dec. 12, 2023

Abstract Bioinsecticides and transgenic crops based on the bacterial pathogen Bacillus thuringiensis (Bt) can effectively control diverse agricultural insect pests, nevertheless, evolution of resistance without obvious fitness costs has seriously eroded sustainable use these Bt products. Recently, it been discovered that an increased titer juvenile hormone (JH) favors host ( Plutella xylostella ) to enhance whilst resisting pathogen, however, underlying regulatory mechanisms JH are obscure. Here, involvement N 6 ‐methyladenosine (m A) RNA modification in modulating availability this process is defined. Specifically, found two m A methyltransferase subunit genes, PxMettl3 PxMettl14 , repress expression a key JH‐degrading enzyme esterase (JHE) induce titer, mitigating associated with robust defense against pathogen. This study identifies as‐yet uncharacterized A‐mediated epigenetic regulator hormones for maintaining during unveils emerging resistance‐related methylation atlas insects, which further expands functional landscape showcases pivotal role regulation host‐pathogen interactions.

Language: Английский

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Infection of neonatal mice with the murine norovirus strain WU23 is a robust model to study norovirus pathogenesis

Lab Animal, Journal Year: 2023, Volume and Issue: 52(6), P. 119 - 129

Published: May 4, 2023

Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they a major in all age groups, infections very young can be quite severe, with annual estimates 50,000-200,000 fatalities children under 5 years old. In spite remarkable burden associated norovirus infections, little is known about pathogenic mechanisms underlying diarrhea, principally because lack tractable small animal models. The development murine (MNV) model nearly two decades ago has facilitated progress understanding host-norovirus interactions strain variability. However, MNV strains tested thus far either do not intestinal or were isolated from extraintestinal tissue, raising concerns translatability research findings to human disease. Consequently, field lacks strong gastroenteritis. Here we provide comprehensive characterization new system for that overcomes prior weaknesses. Specifically, demonstrate WU23 mouse naturally presenting causes transient reduction weight gain acute self-resolving neonatal mice several inbred lines. Moreover, our reveal norovirus-induced infection subepithelial cells intestine systemic spread. Finally, type I interferons (IFNs) critical protect hosts whereas III IFNs exacerbate diarrhea. This latter finding consistent other emerging data implicating exacerbation some viral diseases. should enable detailed investigation mechanisms.

Language: Английский

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