m6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus

Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(1)

Published: April 3, 2023

Abstract Background Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4 + T-cell activation and imbalanced effector differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6 -methyladenosine (m 6 A) modification T-cell-mediated humoral immunity. However, how this biological process contributes to not well understood. In work, we investigated the role of m A methyltransferase like 3 (METTL3) activation, differentiation, SLE pathogenesis both vitro vivo. Methods The expression METTL3 was knocked down enzyme activity inhibited using siRNA catalytic inhibitor, respectively. vivo evaluation inhibition on achieved sheep red blood cell (SRBC)-immunized mouse model chronic graft versus host disease (cGVHD) model. RNA-seq performed identify pathways gene signatures targeted by METTL3. RNA-immunoprecipitation qPCR applied confirm targets. Results defective T cells patients. varied following vitro. Pharmacological promoted influenced cells, predominantly Treg Moreover, increased antibody production aggravated lupus-like phenotype cGVHD mice. Further investigation revealed that reduced Foxp3 enhancing mRNA decay A-dependent manner, hence suppressing differentiation. Conclusion summary, our findings demonstrated required for stabilizing via maintain program. contributed participating imbalance could serve as target therapeutic intervention SLE.

Language: Английский

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NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011808 - e1011808

Published: Dec. 4, 2023

Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and cancer, despite strong prevention treatment efforts. The study the epigenetic modification HBV has become research hotspot, including N 6-methyladenosine (m 6 A) RNA, which plays complex roles in life cycle. In addition to m A modification, 5-methylcytosine 5 C) another eukaryotic mRNA. this study, we explored C methyltransferase demethyltransferase results showed that NSUN2 deficiency could negatively regulate expression while TET2 positively regulates HBV. Subsequently, combined both vitro bisulfite sequencing high-throughput methods determine distribution stoichiometry RNA. Two sites: C2017 C131 with highest-ranking methylation rates were identified, mutations at these two sites lead decreased replication HBV, mutation “fake” site had no effect. Mechanistically, NSUN2-mediated promotes stability addition, compared wild-type HepG2-NTCP cells primary human hepatocytes, level after knockdown decreased, ability mutant infect replicate PHHs was substantially impaired. Similar found experiments using C57BL/6JGpt- Nsun2 +/- mice. Interestingly, also core protein promoted endogenous NSUN2, implied positive feedback loop. summary, our provides an accurate high-resolution profile RNA reveals by maintaining stability.

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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Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107226 - 107226

Published: March 25, 2024

Epstein-Barr virus (EBV) is a human tumor associated with variety of malignancies, including nasopharyngeal carcinoma, gastric cancers, and B-cell lymphomas. N6-methyladenosine (m6A) modifications modulate wide range cellular processes participate in the regulation virus-host cell interactions. Here, we discovered that EBV infection downregulates Toll-like receptor 9 (TLR9) m6A modification levels thus inhibits TLR9 expression. has multiple sites. Knockdown METTL3, an "writer", decreases protein expression by inhibiting its mRNA stability. Mechanistically, nuclear antigen 1 (EBNA1) increases METTL3 degradation via K48-linked ubiquitin-proteasome pathway. Additionally, YTHDF1 was identified as "reader" TLR9, enhancing promoting translation -dependent manner, which suggests "hijacking" host mechanism. Using inhibitor STM2457 TLR9-induced B proliferation Ig secretion, opposes immune responses to assist escape. In clinical lymphoma samples, highly correlated cells infiltration. This study reveals novel mechanism represses important innate immunity molecule through modulating system.

Language: Английский

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