Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules.
DNA, whether it is microbe-derived or host-derived, evokes immune responses when exposed to the cytosol of a cell. We previously reported that DNA-dependent activator of IFN regulatory factors (DAI), also referred to as DLM-1/ZBP1, functions as a DNA sensor that activates the innate immune system. In the present study, we examined the regulation of the complex DNA-sensing system by DAI and other molecules. We first show that DAI directly interacts with DNA in vitro and that it requires three DNA-binding domains for full activation in vivo. We also show that the artificially induced dimerization of DAI results in the DNA-independent activation of type I IFN genes, thereby providing a better understanding for the molecular basis of DAI activation. Furthermore, we provide evidence for the presence of additional DNA sensors, either positively or negatively regulating cytosolic DNA-mediated innate immune responses. These results in toto provide insights into the mechanism of DAI activation and reveal the complex regulatory mechanisms underlying DNA-mediated protective and pathologic immune responses.
Wang
Zhichao
Z
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Choi
Myoung Kwon
MK
Ban
Tatsuma
T
Yanai
Hideyuki
H
Negishi
Hideo
H
Lu
Yan
Y
Tamura
Tomohiko
T
Takaoka
Akinori
A
Nishikura
Kazuko
K
Taniguchi
Tadatsugu
T
D000243:Adenosine Deaminase / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003600:Cytosol; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D019281:Dimerization; D006023:Glycoproteins / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics; D051379:Mice; D016601:RNA-Binding Proteins
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D007370:Interferon Type I; D016601:RNA-Binding Proteins; C402632:Zbp1 protein, mouse; D004247:DNA; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase