Extrachromosomal histone H2B mediates innate antiviral immune responses induced by intracellular double-stranded DNA.
Fragments of double-stranded DNA (dsDNA) forming a right-handed helical structure (B-DNA) stimulate cells to produce type I interferons (IFNs). While an adaptor molecule, IFN-beta promoter stimulator 1 (IPS-1), mediates dsDNA-induced cellular signaling in human cells, the underlying molecular mechanism is not fully understood. Here, we demonstrate that the extrachromosomal histone H2B mediates innate antiviral immune responses in human cells. H2B physically interacts with IPS-1 through the association with a newly identified adaptor, CIAO (COOH-terminal importin 9-related adaptor organizing histone H2B and IPS-1), to transmit the cellular signaling for dsDNA but not immunostimulatory RNA. Extrachromosomal histone H2B was biologically crucial for cell-autonomous responses to protect against multiplication of DNA viruses but not an RNA virus. Thus, the present findings provide evidence indicating that the extrachromosomal histone H2B is engaged in the signaling pathway initiated by dsDNA to trigger antiviral innate immune responses.
Kobiyama
Kouji
K
Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama 236-0004, Japan.
Takeshita
Fumihiko
F
Jounai
Nao
N
Sakaue-Sawano
Asako
A
Miyawaki
Atsushi
A
Ishii
Ken J
KJ
Kawai
Taro
T
Sasaki
Shin
S
Hirano
Hisashi
H
Ishii
Norihisa
N
Okuda
Kenji
K
Suzuki
Koichi
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D004267:DNA Viruses / Q000502:physiology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014709:Vero Cells
D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D006657:Histones; C505371:MAVS protein, human; D016899:Interferon-beta; D004247:DNA