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      RNA modifications: importance in immune cell biology and related diseases

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          Abstract

          RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune cell abnormality in human diseases is also a research focus and progressing rapidly these years. Studies have demonstrated that RNA modifications participate in the multiple biological processes of immune cells, including development, differentiation, activation, migration, and polarization, thereby modulating the immune responses and are involved in some immune related diseases. In this review, we present existing knowledge of the biological functions and underlying mechanisms of RNA modifications, including N 6-methyladenosine (m 6A), 5-methylcytosine (m 5C), N 1-methyladenosine (m 1A), N 7-methylguanosine (m 7G), N 4-acetylcytosine (ac 4C), pseudouridine (Ψ), uridylation, and adenosine-to-inosine (A-to-I) RNA editing, and summarize their critical roles in immune cell biology. Via regulating the biological processes of immune cells, RNA modifications can participate in the pathogenesis of immune related diseases, such as cancers, infection, inflammatory and autoimmune diseases. We further highlight the challenges and future directions based on the existing knowledge. All in all, this review will provide helpful knowledge as well as novel ideas for the researchers in this area.

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          N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

          We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N 6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.
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            N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

            N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.
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              Dynamic RNA Modifications in Gene Expression Regulation

              Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.
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                Author and article information

                Contributors
                wx739976260@foxmail.com
                shiyuling1973@tongji.edu.cn
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                22 September 2022
                22 September 2022
                2022
                : 7
                : 334
                Affiliations
                [1 ]GRID grid.24516.34, ISNI 0000000123704535, Department of Dermatology, Shanghai Skin Disease Hospital, , Tongji University School of Medicine, ; 1278 Baode Road, Jing’an District, Shanghai, 200443 China
                [2 ]GRID grid.24516.34, ISNI 0000000123704535, Institute of Psoriasis, , Tongji University School of Medicine, ; Shanghai, China
                [3 ]GRID grid.24516.34, ISNI 0000000123704535, Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, , Tongji University School of Medicine, ; Shanghai, 200433 China
                Author information
                http://orcid.org/0000-0002-1273-7881
                Article
                1175
                10.1038/s41392-022-01175-9
                9499983
                36138023
                7ce080ab-20c2-4d28-bf8c-7c216f472990
                © The Author(s) 2022

                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
                : 13 June 2022
                : 23 August 2022
                : 31 August 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81872522,82073429
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2022

                biochemistry,immunology
                biochemistry, immunology

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