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Pooled CRISPR screening identifies m6A as a positive regulator of macrophage activation.

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机构： [1]Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and RelatedGenes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2]Shanghai Jiao Tong University School of Medicine–Yale Institute for ImmuneMetabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025,China [3]Department of Pediatrics and Key Laboratory of Birth Defects and RelatedDiseases of Women and Children of MOE, West China Second University Hospital,Sichuan University, China [4]Hefei National Laboratory for Physical Sciences at Microscale,the Chinese Academy of Sciences Key Laboratory of Innate Immunityand Chronic Disease, School of Basic Medical Sciences, Division of Life Sciencesand Medicine, University of Science and Technology of China, 230027 Hefei,China [5]Institute for Advanced Studies, State Key Laboratory of Virology, College ofLife Sciences, Wuhan University, Wuhan 430072, China [6]State Key Laboratory ofMolecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center forExcellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai200031, China [7]University of Chinese Academy of Sciences, Beijing 100049, China [8]School of Life Sciences, Peking University, Beijing 100871, China [9]Department ofLiver Surgery and State Key Laboratory of Oncogenes and Related Genes, Ren JiHospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127,China [10]Department of Immunobiology, Yale University School of Medicine,New Haven, CT 06520-8055, USA [11]Howard Hughes Medical Institute, Yale UniversitySchool of Medicine, New Haven, CT 06520-8055, USA

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m6A RNA modification is implicated in multiple cellular responses. However, its function in the innate immune cells is poorly understood. Here, we identified major m6A "writers" as the top candidate genes regulating macrophage activation by LPS in an RNA binding protein focused CRISPR screening. We have confirmed that Mettl3-deficient macrophages exhibited reduced TNF-α production upon LPS stimulation in vitro. Consistently, Mettl3flox/flox;Lyzm-Cre mice displayed increased susceptibility to bacterial infection and showed faster tumor growth. Mechanistically, the transcripts of the Irakm gene encoding a negative regulator of TLR4 signaling were highly decorated by m6A modification. METTL3 deficiency led to the loss of m6A modification on Irakm mRNA and slowed down its degradation, resulting in a higher level of IRAKM, which ultimately suppressed TLR signaling-mediated macrophage activation. Our findings demonstrate a previously unknown role for METTL3-mediated m6A modification in innate immune responses and implicate the m6A machinery as a potential cancer immunotherapy target. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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第一作者：

第一作者机构： [1]Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and RelatedGenes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2]Shanghai Jiao Tong University School of Medicine–Yale Institute for ImmuneMetabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025,China [3]Department of Pediatrics and Key Laboratory of Birth Defects and RelatedDiseases of Women and Children of MOE, West China Second University Hospital,Sichuan University, China

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通讯作者：

通讯机构： [1]Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and RelatedGenes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2]Shanghai Jiao Tong University School of Medicine–Yale Institute for ImmuneMetabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025,China [9]Department ofLiver Surgery and State Key Laboratory of Oncogenes and Related Genes, Ren JiHospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127,China [10]Department of Immunobiology, Yale University School of Medicine,New Haven, CT 06520-8055, USA [11]Howard Hughes Medical Institute, Yale UniversitySchool of Medicine, New Haven, CT 06520-8055, USA

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