Lastly, PKZ is a fish protein related to mammalian PKR, also involved in antiviral immunity. E3L is a poxvirus protein known to antagonise this host response. ADAR1 and ZBP1 are mammalian proteins implicated in antiviral innate immune responses. ZBDs have been identified in four proteins: ADAR1, ZBP1, E3L and PKZ (Athanasiadis, 2012). This 78‐amino‐acid domain is also referred to as Zα or Zβ, and subsequent work showed that it not only binds to Z‐DNA but also to Z‐RNA (Brown et al, 2000 Placido et al, 2007). Physiological functions of Z‐RNA remain unknown.Įarly biochemical and structural studies identified a protein fold called Z‐binding domain (ZBD) that specifically binds to Z‐DNA but not to B‐DNA (Herbert et al, 1993 Schwartz et al, 1999). Z‐DNA is believed to play a role in transcription by relieving torsional strain induced within the DNA template by the movement of RNA polymerases, and Z‐DNA may also promote genetic instability (Rich & Zhang, 2003 Wang & Vasquez, 2007).
However, biological functions of the Z‐conformation are only partially understood (Rich & Zhang, 2003 Wang & Vasquez, 2007). Antibodies raised against Z‐form RNA or DNA stain mammalian cells and chromosomes, respectively, suggesting that nucleic acids in this unusual conformation occur naturally in cells (Viegas‐Péquignot et al, 1983 Zarling et al, 1990).
Both DNA and RNA can also adopt a Z‐form double helix that is characterised by a left‐handed helical arrangement, a zigzag pattern of the phosphodiester backbone and the absence of major grooves (Wang et al, 1979 Hall et al, 1984 Rich & Zhang, 2003). Double‐stranded (ds) DNA typically adopts the so‐called B‐conformation, while dsRNA is usually in the A‐conformation. Nucleic acids form double‐stranded helices. These observations show that Z‐ RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP1. Intact ZBP1‐ ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross‐linked to endogenous RNA. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. 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. These include ZBP1 (also known as DAI or DLM‐1), which induces necroptosis, an inflammatory form of cell death. Z‐ DNA/ RNA is recognised by Z‐binding domains ( ZBDs), which are present in proteins implicated in antiviral immunity. Double‐stranded DNA and RNA adopt different helical conformations, including the unusual Z‐conformation. Nucleic acids are potent triggers for innate immunity.
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