title: H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1.
abstract: The H3K4me3 demethylase Kdm5a regulates gene transcription and is implicated in carcinogenesis. However, the role of Kdm5a in innate immune response remains poorly understood. Here, we demonstrate that Kdm5a deficiency impairs activation of natural killer (NK) cells, with decreased IFN-γ production. Accordingly, Kdm5a(-/-) mice are highly susceptible to Listeria monocytogenes (Lm) infection. During NK cell activation, loss of Kdm5a profoundly impairs phosphorylation and nuclear localization of STAT4, along with increased expression of suppressor of cytokine signaling 1 (SOCS1). Mechanistic studies reveal that Kdm5a associates with p50 and binds to the Socs1 promoter region in resting NK cells, leading to a substantial decrease in H3K4me3 modification and repressive chromatin configuration at the Socs1 promoter. Thus, Kdm5a is required for priming activation of NK cells by suppressing the suppressor, SOCS1. Our study provides insights into the epigenetic regulation of innate immune response of NK cells.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Zhao
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qicong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D060467:Disease Resistance / Q000187:drug effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018664:Interleukin-12 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D056485:Retinoblastoma-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism*; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D052002:NF-kappa B p50 Subunit; D050797:STAT4 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D018664:Interleukin-12; C577458:KDM5A protein, mouse; D056485:Retinoblastoma-Binding Protein 2; D053614:Janus Kinase 2; D008239:Lysine