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.

Insights from Sannula Kesavardhana and Thirumala-Devi Kanneganti.

Schematic representation of ZBP1 activation promoting cell death and inflammation. Z-RNAs from IAV or murine cytomegalovirus (MCMV) or dsRNAs formed by ERVs stimulate Zα domain–dependent activation of ZBP1. When RIPK1 is deleted in keratinocytes or the RHIM domain of RIPK1 is mutated, ERV-mediated activation of ZBP1 promotes RIPK3-MLKL–mediated necroptosis. Activation of ZBP1 by Z-RNAs from IAV triggers assembly of the PANoptosome, which engage pyroptosis, apoptosis, and necroptosis (PANoptosis). CARD, caspase activation and recruitment domain; CASP, caspase; DD, death domain; DED, death effector domain; LRR, leucine-rich repeat; PYD, pyrin domain.