H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1

Dezhi Zhao; Qian Zhang; Yiqi Liu; Xia Li; Kai Zhao; Yuanyuan Ding; Zhiqing Li; Qicong Shen; Chunmei Wang; Nan Li; Xuetao Cao

doi:10.1016/j.celrep.2016.03.035

H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1

Cell Rep. 2016 Apr 12;15(2):288-99. doi: 10.1016/j.celrep.2016.03.035. Epub 2016 Mar 31.

Authors

Dezhi Zhao¹, Qian Zhang², Yiqi Liu¹, Xia Li¹, Kai Zhao³, Yuanyuan Ding¹, Zhiqing Li¹, Qicong Shen², Chunmei Wang³, Nan Li², Xuetao Cao⁴

Affiliations

¹ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
³ National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China.
⁴ 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.

PMID: 27050510
DOI: 10.1016/j.celrep.2016.03.035

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Chromatin / metabolism
Disease Resistance / drug effects
HEK293 Cells
Histones / metabolism*
Humans
Inflammation / pathology
Interleukin-12 / pharmacology
Janus Kinase 2 / metabolism
Killer Cells, Natural / drug effects
Killer Cells, Natural / immunology*
Listeria monocytogenes / immunology
Listeriosis / immunology
Listeriosis / microbiology
Lymphocyte Activation* / drug effects
Lysine / metabolism*
Methylation / drug effects
Mice
NF-kappa B p50 Subunit / metabolism*
Phosphorylation / drug effects
Promoter Regions, Genetic / genetics
Protein Transport / drug effects
Retinoblastoma-Binding Protein 2 / deficiency
Retinoblastoma-Binding Protein 2 / metabolism*
STAT4 Transcription Factor / metabolism
Signal Transduction / drug effects
Suppressor of Cytokine Signaling 1 Protein / genetics
Suppressor of Cytokine Signaling 1 Protein / metabolism*

Substances

Chromatin
Histones
NF-kappa B p50 Subunit
STAT4 Transcription Factor
Socs1 protein, mouse
Suppressor of Cytokine Signaling 1 Protein
Interleukin-12
KDM5A protein, mouse
Retinoblastoma-Binding Protein 2
Janus Kinase 2
Lysine