DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response

Abstract

Central to innate immunity is the sensing of pathogen-associated molecular patterns by cytosolic and membrane-associated receptors. In particular, DNA is a potent activator of immune responses during infection or tissue damage, and evidence indicates that, in addition to the membrane-associated Toll-like receptor 9, an unidentified cytosolic DNA sensor(s) can activate type I interferon (IFN) and other immune responses. Here we report on a candidate DNA sensor, previously named DLM-1 (also called Z-DNA binding protein 1 (ZBP1)), for which biological function had remained unknown; we now propose the alternative name DAI (DNA-dependent activator of IFN-regulatory factors). The artificial expression of otherwise IFN-inducible DAI (DLM-1/ZBP1) in mouse fibroblasts selectively enhances the DNA-mediated induction of type I IFN and other genes involved in innate immunity. On the other hand, RNA interference of messenger RNA for DAI (DLM-1/ZBP1) in cells inhibits this gene induction programme upon stimulation by DNA from various sources. Moreover, DAI (DLM-1/ZBP1) binds to double-stranded DNA and, by doing so, enhances its association with the IRF3 transcription factor and the TBK1 serine/threonine kinase. These observations underscore an integral role of DAI (DLM-1/ZBP1) in the DNA-mediated activation of innate immune responses, and may offer new insight into the signalling mechanisms underlying DNA-associated antimicrobial immunity and autoimmune disorders.

The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

“…Although ISD contains no contiguous CpG motifs, we wanted to rule out the possibility that TLR9 contributes to ISD recognition by applying ISD in the absence of transfection reagents [10,15]. This treatment did not trigger IFN-b production in RAW264.7 cells ( Fig.…”

“…TLR9 activation requires acidification of the endosome and subsequent proteolytic cleavage by cathepsins, which can be blocked by chloroquine or Z-FA-FMK, respectively [18]. CpG and LPS trigger the production of DAI (DLM-1/ZBP1), an IFN-induced gene that was used as an indirect read-out for the IFN response [15]. In agreement with plasma membrane localization of TLR4, LPS-mediated DAI production was unaffected by chloroquine or Z-FA-FMK (Fig.…”

“…IL-1b secretion is governed by the DNA sensor AIM2 that has recently been identified [11][12][13][14]. IFN-b production is regulated by the DNA-dependent activator of IFN-regulatory factors (DAI, formerly known as DLM-1/ZBP1) [15] and as-yet unknown DNA sensors [16,17]. With regard to the IFN pathway, it has been suggested that the B-conformation of DNA is stimulatory, whereas Z-DNA is not [9].…”

RIP kinases: key decision makers in cell death and innate immunity

“…112 DAI contains two RHIM motifs that allows it to interact with RIP1 and RIP3 and trigger downstream activation of NFkB 113,114 (Figure 3). The interaction of DAI with RIP3 also sensitizes cells to murine cytomegalovirus (MCMV)-induced necrosis with DAI-and RIP3-deficient cells being resistant to this form of death.…”

DNA Vaccines for Prostate Cancer

“…In addition, the presence of unmethylated CpG motifs present in the bacterial DNA may further serve as an immune stimulant by TLR9 activation [11]. Moreover, recent studies suggest that the presence of specific intracellular DNA sensors, including DAI (DNA-dependent activator of IFN-regulatory factors [12]), and members of the interferon-inducible gene family (IF116, AIM2 [13]) can recognize double stranded cytosolic DNA and elicit inflammatory type immune responses via activation of STING (stimulator of interferon genes) independent of TLR9 [14–16]. By one or both of these mechanisms, TLR activation or intracellular DNA sensors, the bacterial DNA itself may act as a vaccine adjuvant [17].…”