Rb selectively inhibits innate IFN-β production by enhancing deacetylation of IFN-β promoter through HDAC1 and HDAC8.
Type I IFN production is tightly controlled by host to generate efficient viral clearance without harmful immunopathology or induction of autoimmune disorders. Epigenetic regulation of type I IFN production in innate immunity and inflammatory disorders remains to be fully understood. Several tumor suppressors have been shown to regulate immune response and inflammation. However, the non-classical functions of tumor suppressors in innate immunity and inflammatory diseases need further identification. Here we report retinoblastoma protein (Rb) deficiency selectively enhanced TLR- and virus-triggered production of IFN-β which thus induced more IFN-α generation in the later phase of innate stimuli, but had no effect on the production of TNF, IL-6 and early phase IFN-α in macrophages. Rb1(fl/fl)Lyz2cre(+) Rb-deficient mice exhibited more resistant to lethal virus infection and more effective clearance of influenza virus. Rb selectively bound Ifnb1 enhancer region, but not the promoter of Ifna4, Tnf and Il6, by interacting with c-Jun, the component of IFN-β enhanceosome. Then Rb recruited HDAC1 and HDAC8 to attenuate acetylation of Histone H3/H4 in Ifnb1 promoter, resulting in suppression of Ifnb1 transcription. Therefore, Rb selectively inhibits innate IFN-β production by enhancing deacetylation of Ifnb1 promoter, exhibiting a previous unknown non-classical role in innate immunity, which also suggests a role of Rb in the regulation of type I IFN production in inflammatory or autoimmune diseases.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Jun
J
Meng
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Xingguang
X
Liu
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Peng
P
Zhang
Department of Reproductive Endocrinology, International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
Dong
D
Li
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Sheng
S
Xu
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Qingqing
Q
Zhou
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Meng
M
Guo
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Wanwan
W
Huai
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Xiang
X
Chen
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Quanxing
Q
Wang
National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Nan
N
Li
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China. Electronic address: caoxt@immunol.org.
Xuetao
X
Cao
D000107:Acetylation; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology
D006657:Histones; D016898:Interferon-alpha; D015850:Interleukin-6; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D016899:Interferon-beta; C000603105:HDAC8 protein, mouse; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
Histone deacetylase; IFN-β; Inflammation; Innate immunity; Retinoblastoma protein