Sensing of viral and endogenous RNA by ZBP 1/ DAI induces necroptosis

Abstract

Nucleic acids are potent triggers for innate immunity. Double‐stranded DNA and RNA adopt different helical conformations, including the unusual Z‐conformation. Z‐DNA/RNA is recognised by Z‐binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM‐1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock‐in models, we report that mutation of key amino acids involved in Z‐DNA/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Intact ZBP1‐ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross‐linked to endogenous RNA. These observations show that Z‐RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP1.

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

“…We and other groups identified ZBP1 as a sensor of viral RNA (Maelfait et al, 2017;Sridharan et al, 2017;Thapa et al, 2016). Our current data bring forward the hypothesis that the detection of endogenous nucleic acids by ZBP1 contributes to inflammatory skin disease.…”

“…ZBP1 contains two tandem N-terminal Z-form nucleic acid binding (Zα)-domains, which specifically interact with doublestranded (ds) nucleic acid helices in the Z-conformation, including Z-RNA and Z-DNA (Herbert, 2019). Others and our group have shown that engagement of ZBP1 upon virus infection crucially depended on nucleic acid sensing by intact Zα-domains (Maelfait et al, 2017;Sridharan et al, 2017;Thapa et al, 2016). The identity of viral ZBP1 agonists remains uncertain, and viral ribonucleoprotein complexes, RNA genomes, or viral transcripts have been suggested to interact with the Zα-domains of ZBP1 (Guo et al, 2018;Kesavardhana et al, 2017;Maelfait et al, 2017;Sridharan et al, 2017;Thapa et al, 2016;Zhang et al, 2020).…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…Notably, DAI has recently been shown to recognize viral RNA in addition to its role in DNA sensing to induce necroptosis (Maelfait et al, 2017; Thapa et al, 2016). The ability of STING to potentiate signals from many of these DNA sensors and bind CDNs places it central to the DNA sensing pathway for viral and bacterial infections.…”

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…A series of gene knockout studies in mice have shown that caspase‐8 and receptor‐interacting protein kinase 1 (RIPK1) inhibit the activation of necroptosis mediated by Z‐DNA binding protein 1 (ZBP1), which is emerging as an important regulator of cell death and inflammatory responses . ZBP1 contains a domain that binds viral and endogenous DNA and RNA molecules that adopt a Z‐form (left‐handed double helix with zigzag pattern) . The involvement of ZBP1 in these experimental skin disease models points to important roles of endogenous nucleic acid species as initiators of skin inflammation.…”

“…[74][75][76] ZBP1 contains a domain that binds viral and endogenous DNA and RNA molecules that adopt a Z-form (left-handed double helix with zigzag pattern). [76,77] The involvement of ZBP1 in these experimental skin disease models points to important roles of endogenous nucleic acid species as initiators of skin inflammation. The breakdown of the nucleus during cornification is a candidate starting point of nucleic acid-triggered pro-inflammatory processes.…”