Condensin Smc4 promotes inflammatory innate immune response by epigenetically enhancing NEMO transcription

Qinlan Wang; Chunmei Wang; Nan Li; Xingguang Liu; Wenhui Ren; Qingqing Wang; Xuetao Cao

doi:10.1016/j.jaut.2018.05.004

Condensin Smc4 promotes inflammatory innate immune response by epigenetically enhancing NEMO transcription

J Autoimmun. 2018 Aug:92:67-76. doi: 10.1016/j.jaut.2018.05.004. Epub 2018 May 24.

Authors

Qinlan Wang¹, Chunmei Wang², Nan Li³, Xingguang Liu³, Wenhui Ren³, Qingqing Wang¹, Xuetao Cao⁴

Affiliations

¹ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
³ National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
⁴ Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: caoxt@immunol.org.

PMID: 29803706
DOI: 10.1016/j.jaut.2018.05.004

Abstract

Structural maintenance of chromosome (Smc) protein complex (condensin) plays a central role in organizing and compacting chromosomes, which determines DNA-binding activity and gene expression; however, the role of condensin Smc in innate immunity and inflammation remains largely unknown. Through a high-throughput screening of the epigenetic modifiers, we identified Smc4, a core subunit of condensin, to potentially promote inflammatory innate immune response. Knockdown or deficiency of Smc4 inhibited TLR- or virus-triggered production of proinflammatory cytokines IL-6, TNF-α and IFN-β in macrophages. Mice with Smc4 knockdown were less susceptible to sepsis. Mechanistically, Smc4 enhanced NEMO transcription by recruiting H4K5ac to and increasing H4K5 acetylation of nemo promoter, leading to innate signals-triggered more potent activation of NF-κB and IRF3 pathways. Therefore, Smc4 promotes inflammatory innate immune responses by enhancing NEMO transcription, and our data add insight to epigenetic regulation of innate immunity and inflammation, and outline potential target for controlling inflammatory diseases.

Keywords: Epigenetic regulation; Inflammation; Innate immunity; NEMO; Smc4.

Publication types

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

MeSH terms

Acetylation
Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism*
Animals
Cells, Cultured
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
Clustered Regularly Interspaced Short Palindromic Repeats
Cytokines / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Epigenesis, Genetic
Immunity, Innate
Inflammation / metabolism*
Inflammation Mediators / metabolism
Interferon Regulatory Factor-3 / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Macrophages, Peritoneal / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
NF-kappa B / metabolism
Promoter Regions, Genetic / genetics
RNA, Small Interfering / genetics
Signal Transduction
Transcriptional Activation

Substances

Chromosomal Proteins, Non-Histone
Cytokines
DNA-Binding Proteins
Inflammation Mediators
Interferon Regulatory Factor-3
Intracellular Signaling Peptides and Proteins
Irf3 protein, mouse
Multiprotein Complexes
NEMO protein, mouse
NF-kappa B
RNA, Small Interfering
SMC4 protein, mouse
condensin complexes
Adenosine Triphosphatases