ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease

Abstract

ZBP1 triggers NLRP3 inflammasome activation/pyroptosis, apoptosis, and necroptosis; the specific ligand for ZBP1 activation remains ambiguous. Recent studies, including Devos et al. in this issue of JEM (https://doi.org/10.1084/jem.20191913), collectively suggest that ZBP1 sensing Z-nucleic acids is critical for cell death/inflammatory disease.

The regulation of the ZBP1‐NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis)

“…74 These data suggest that ZBP1 can directly sense endogenous transcripts during development to induce programmed cell death and inflammation. 63 Interestingly, while around 85% of Zbp1 -/-Ripk1 E-KO and Zbp1 mR1/mR1 Ripk1 E-KO mice remain healthy for more than 40 weeks, approximately 75% of the Zbp1 mZα2/mZα2 Ripk1 E-KO mice develop mild skin inflammation at the age of 40 weeks, suggesting that ZBP1 may function as a adapter protein downstream of some factors. 74 In addition to its functions in infection and organismal development, ZBP1 is also involved in inflammatory bowel diseases (IBD).…”

“…61 Later, however, it was demonstrated that loss of ZBP1 has no effect on DNA-induced immune responses. 62,63…”

“…In spite of the critical function of ZBP1 in host defense, the natural ligand for ZBP1 has not been fully established. 63 Inhibiting RNA synthesis but not translation can block MCMV-M45mutRHIM-induced necroptosis. 80 Likewise, suppressing transcription but not viral DNA replication is able to abolish the ICP6-RHIM-mutated HSV1induced cell death.…”

“…74,75,87,88 More studies are required to differentiate the contribution of viral RNA and endogenous RNA in activating ZBP1 during virus infection. 63 Moreover, it is worth noting that even though ZBP1 contains two Zα domains and two RHIMs, only one of each has been found to be functional. 66,71,78,80 So far, only Zα2 is known to be essential for recognizing viral infection and RHIM1 is known to mediate signal transduction by interacting with RIPK3 and/or RIPK1.…”

PANoptosis in microbial infection

“…Recently, ZBP1 has been identified as a sensor of IAV vRNPs that triggers PANoptosis ( Figure 2 ) [ 18 ]. During infection, ZBP1 interacts with RIPK3 via the RHIM domain and recruits caspase-8 and the NLRP3 inflammasome sensor to promote assembly of a PANoptosome complex that drives PANoptosis [ 18 , 41 , 42 , 43 ]. The ZBP1-dependent PANoptosome is required for NLRP3– and capsase-1–dependent inflammasome activation, pyroptosis, and maturation of proinflammatory cytokines including IL-1β and IL-18 during IAV infection.…”