RESEARCH ARTICLE

Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter

  • Donghao Sun ,
  • Xuetao Cao ,
  • Chunmei Wang
Expand
  • Department of Immunology and Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China

Received date: 26 Jun 2018

Accepted date: 28 Sep 2018

Published date: 12 Apr 2019

Copyright

2018 The Author(s) 2018

Abstract

Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a nontraditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.

Cite this article

Donghao Sun , Xuetao Cao , Chunmei Wang . Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter[J]. Protein & Cell, 2019 , 10(4) : 285 -294 . DOI: 10.1007/s13238-018-0581-0

1
Aranda S, Mas G, Di Croce L (2015) Regulation of gene transcription by Polycomb proteins. Sci Adv 1:e1500737

DOI

2
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

DOI

3
Cao X (2016) Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat Rev Immunol 16:35–50

DOI

4
Chen WY, Zhang XY, Liu T, Liu Y, Zhao YS, Pang D (2017) Chromobox homolog 2 protein: a novel biomarker for predicting prognosis and Taxol sensitivity in patients with breast cancer. Oncol Lett 13:1149–1156

DOI

5
Chung CY, Sun Z, Mullokandov G, Bosch A, Qadeer ZA, Cihan E, Rapp Z, Parsons R, Aguirre-Ghiso JA, Farias EF (2016) Cbx8 acts non-canonically with Wdr5 to promote mammary tumorigenesis. Cell Rep 16:472–486

DOI

6
Clermont PL, Crea F, Chiang YT, Lin D, Zhang A, Wang JZ, Parolia A, Wu R, Xue H, Wang Y (2016) Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer. Clin Epigenet 8:16

DOI

7
Di Croce L, Helin K (2013) Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol 20:1147–1155

DOI

8
Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U, Sepe R, Palma G, Troncone G, Scarfo M (2012) CBX7 is a tumor suppressor in mice and humans. J Clin Investig 122:612–623

DOI

9
Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D (2012) PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell 45:344–356

DOI

10
Garcia-Sastre A (2017) Ten strategies of interferon evasion by viruses. Cell Host Microbe 22:176–184

DOI

11
Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA 104:18439–18444

DOI

12
Iwasaki A, Pillai PS (2014) Innate immunity to influenza virus infection. Nat Rev Immunol 14:315–328

DOI

13
Jiang M, Zhang S, Yang Z, Lin H, Zhu J, Liu L, Wang W, Liu S, Liu W, Ma Y (2018) Self-recognition of an inducible host lncRNA by RIG-I feedback restricts innate immune response. Cell 173(906–919):e913

DOI

14
Katoh-Fukui Y, Tsuchiya R, Shiroishi T, Nakahara Y, Hashimoto N, Noguchi K, Higashinakagawa T (1998) Male-to-female sex reversal in M33 mutant mice. Nature 393:688–692

DOI

15
Kawaguchi T, Machida S, Kurumizaka H, Tagami H, Nakayama JI (2017) Phosphorylation of CBX2 controls its nucleosome-binding specificity. J Biochem 162:343–355

DOI

16
Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

DOI

17
Li J, Li Y, Cao Y, Yuan M, Gao Z, Guo X, Zhu F, Wang Y, Xu J (2014a) Polycomb chromobox (Cbx) 7 modulates activationinduced CD4+ T cell apoptosis. Arch Biochem Biophys 564:184–188

DOI

18
Li J, Xu Y, Long XD, Wang W, Jiao HK, Mei Z, Yin QQ, Ma LN, Zhou AW, Wang LS (2014b) Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell 25:118–131

DOI

19
Li X, Zhang Q, Ding Y, Liu Y, Zhao D, Zhao K, Shen Q, Liu X, Zhu X, Li N (2016) Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol 17:806–815

DOI

20
Marcos-Villar L, Diaz-Colunga J, Sandoval J, Zamarreno N, Landeras-Bueno S, Esteller M, Falcon A, Nieto A (2018) Epigenetic control of influenza virus: role of H3K79 methylation in interferon-induced antiviral response. Sci Rep 8:1230

DOI

21
McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A (2015) Type I interferons in infectious disease. Nat Rev Immunol 15:87–103

DOI

22
Santanach A, Blanco E, Jiang H, Molloy KR, Sanso M, LaCava J, Morey L, Di Croce L (2017) The Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity. Nat Commun 8:1235

DOI

23
Simon JA, Kingston RE (2013) Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell 49:808–824

DOI

24
Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6:846–856

DOI

25
Wang C, Wang Q, Xu X, Xie B, Zhao Y, Li N, Cao X (2017) The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3. J Exp Med 214:3597–3610

DOI

26
Wang X, Li L, Wu Y, Zhang R, Zhang M, Liao D, Wang G, Qin G, Xu RH, Kang T (2016) CBX4 suppresses metastasis via recruitment of HDAC3 to the Runx2 promoter in colorectal carcinoma. Cancer Res 76:7277–7289

DOI

27
Wu J, Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol 32:461–488

DOI

28
Yoshida K, Maekawa T, Zhu Y, Renard-Guillet C, Chatton B, Inoue K, Uchiyama T, Ishibashi K, Yamada T, Ohno N (2015) The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat Immunol 16:1034–1043

DOI

29
Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, Zhao D, Liu Y, Wang C, Zhang X (2015) Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525:389–393

DOI

30
Zhang XW, Zhang L, Qin W, Yao XH, Zheng LZ, Liu X, Li J, Guo WJ (2010) Oncogenic role of the chromobox protein CBX7 in gastric cancer. J Exp Clin Cancer Res 29:114

DOI

Outlines

/