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Comment
. 2017 Sep 1;36(17):2470-2472.
doi: 10.15252/embj.201797845. Epub 2017 Aug 18.

Live and Let Die: ZBP1 Senses Viral and Cellular RNAs to Trigger Necroptosis

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Live and Let Die: ZBP1 Senses Viral and Cellular RNAs to Trigger Necroptosis

Sonia Assil et al. EMBO J. .
Free PMC article

Abstract

Necroptosis is a programmed form of inflammatory cell death involved in various pathologies, such as viral infections. In two new papers published in The EMBO Journal and EMBO Reports, Z‐DNA binding protein 1 (ZBP1) is now shown to sense RNAs during viral infection or after caspase inhibition and activate necroptosis. This may suggest that Z‐RNAs are molecular patterns for activation of necroptosis.

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Figure 1
Figure 1. Model for ZBP1‐mediated activation of necroptosis by recognition of RNAs
Purple circles (1–5) show ZBP1‐mediated activation of necroptosis by MCMV infection. (1, 2) Viral entry, nuclear replication, and production of progeny virus. (3) An integral part of the replication cycle is IE3‐dependent viral RNA transcription. (4) ZBP1 senses viral RNA, thus stimulating interaction with RIPK3 through its RHIM A domain. (5) RIPK3 activation induces phosphorylation of MLKL, leading to activation of necroptosis. The viral protein M36 inhibits caspase‐8‐mediated blocking of necroptosis, while M45 inhibits ZBP1–RIPK3 interaction. ZBP1 expression can be stimulated by type I IFN that can be produced, for example, after sensing of viral DNA by the cGAS‐STING pathway. Blue circles (1′–3′) show ZBP1‐mediated activation of necroptosis by endogenous RNAs upon caspase blockade. (1′) In the presence of zVAD, a caspase inhibitor, ZBP1 activates necroptosis. (2′) This is likely mediated through sensing of endogenous RNAs (Z‐RNAs?). (3′) Caspase‐inhibition‐induced necroptosis involved both RIPK3 and RIPK1.

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