METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. Dysregulated cytokine secretion and signal transduction mechanisms via intestinal epithelial cells are involved in IBD pathogenesis, in which the transcription factor NF-κB plays a critical role. In this study, METTL3, which plays a key role in inflammation regulation, has been recognized significantly up-regulated in IBD samples, DSS-induced IBD mice, and LPS-treated MODE-K cells. Within LPS-treated MODE-K cells, METTL3 knockdown promoted cell viability, inhibited cell apoptosis, decreased apoptotic caspase3/9 cleavage, and decreased the levels of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-18) and inflammatory enzymes (COX-2 and iNOS). Under the same conditions, METTL3 knockdown inhibited, whereas METTL3 overexpression promoted p65 phosphorylation in MODE-K cells; NF-κB inhibitor JSH-23 partially abolished the promotive effects of METTL3 overexpression upon p65 phosphorylation. Consistently, the effects of METTL3 overexpression upon LPS-stimulated MODE-K cells were partially abolished by JSH-23. Lastly, METTL3 knockdown in DSS-induced IBD mice significantly ameliorated DSS-induced IBD and inhibited DSS-induced p65 phosphorylation. In conclusion, METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. The NF-κB signaling might be involved, and the regulatory mechanism remains to be investigated in our future study.

Related collections

Most cited references 42

Record: found
Abstract: found
Article: not found

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer.

Huilin Huang, Hengyou Weng, Jianjun Chen (2020)

N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.

0 comments Cited 504 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.

J Bokar, M Shambaugh, D Polayes … (1997)

The methylation of internal adenosine residues in eukaryotic mRNA, forming N6-methyladenosine (m6A), is catalyzed by a complex multicomponent enzyme. Previous studies suggested that m6A affects the efficiency of mRNA processing or transport, although the mechanism by which this occurs is not known. As a step toward better understanding the mechanism and function of this ubiquitous posttranscriptional modification, we have shown that HeLa mRNA (N6-adenosine)-methyltransferase requires at least two separate protein factors, MT-A and MT-B, and MT-A contains the AdoMet binding site on a 70-kDa subunit (MT-A70). MT-A70 was purified by conventional chromatography and electrophoresis, and was microsequenced. The peptide sequence was used to design a degenerate oligodeoxynucleotide that in turn was used to isolate the cDNA clone coding for MT-A70 from a HeLa cDNA library. Recombinant MT-A70 was expressed as a fusion protein in bacteria and was used to generate anti-MT-A70 antisera in rabbits. These antisera recognize MT-A70 in HeLa nuclear extracts by western blot and are capable of depleting (N6-adenosine)-methyltransferase activity from HeLa nuclear extract, confirming that MT-A70 is a critical subunit of (N6-adenosine)-methyltransferase. Northern blot analysis reveals that MT-A70 mRNA is present in a wide variety of human tissues and may undergo alternative splicing. MT-A70 cDNA probe hybridizes to a 2.0-kilobase (kb) polyadenylated RNA isolated from HeLa cells, whereas it hybridizes to two predominant RNA species (approximately 2.0 kb and 3.0 kb) using mRNA isolated from six different human tissues. Analysis of the cDNA sequence indicates that it codes for a 580-amino acid protein with a predicted MW = 65 kDa. The predicted protein contains sequences similar to consensus methylation motifs I and II identified in prokaryotic DNA (N6-adenosine)-methyltransferases, suggesting the functional conservation of peptide motifs. MT-A70 also contains a long region of homology to the yeast protein SPO8, which is involved in induction of sporulation by an unknown mechanism.

0 comments Cited 298 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: not found
Article: not found

Inflammatory bowel disease.

Daniel K. Podolsky, Peter Moses (2002)

0 comments Cited 216 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Lianwen Yuan:

ORCID: http://orcid.org/0000-0001-5089-5066

yuanlianwen@csu.edu.cn

Journal

Journal ID (nlm-ta): Cell Death Discov

Journal ID (iso-abbrev): Cell Death Discov

Title: Cell Death Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2058-7716

Publication date (Electronic): 14 February 2022

Publication date PMC-release: 14 February 2022

Publication date Collection: 2022

Volume: 8

Electronic Location Identifier: 62

Affiliations

GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Geriatric Surgery, The Second Xiangya Hospital, , Central South University, ; Changsha, Hunan China

Author information

Lichao Yang http://orcid.org/0000-0002-6897-1503

Lianwen Yuan http://orcid.org/0000-0001-5089-5066

Article

Publisher ID: 849

DOI: 10.1038/s41420-022-00849-1

PMC ID: 8844074

PubMed ID: 35165276

SO-VID: 6a737e99-4bb1-411a-a8a3-f4991317acb4

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 September 2021

Date revision received : 12 January 2022

Date accepted : 25 January 2022

Funding

Funded by: This work was supported by the National Natural Science Foundation of China (Grant NO.81970493);the Natural Science Foundation of Hunan Province of China (Grant NO.2021JJ30973);and the Fundamental Research Funds for the Central Universities of Central South University.