Gut stem cell necroptosis by genome instability triggers bowel inflammation

Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development

“…The N122 and Y126 residues in the Za2 domain of ZBP1 are essential for the Z-nucleic acid interaction, and mutations in these positions were shown to abolish the Z-nucleic acid-binding potential of ZBP1 (12). is essential for activating cell death and inflammation (24)(25)(26). These findings from independent groups corroborate our results presented here and also our previous reports on ZBP1 sensing of an RNA virus (IAV) to activate cell death and inflammation (5,6,(24)(25)(26).…”

“…is essential for activating cell death and inflammation (24)(25)(26). These findings from independent groups corroborate our results presented here and also our previous reports on ZBP1 sensing of an RNA virus (IAV) to activate cell death and inflammation (5,6,(24)(25)(26). Overall, our findings, in conjunction with these new studies, establish a critical and specific role for the Za2 domain of ZBP1 in regulating PANoptosis, inflammation, and perinatal lethality in mice and provide genetic evidence for the functional relevance of Znucleic acid-binding domains in vivo.…”

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

“…Discovery of these dynamics uncovered a previously unknown homeostatic regulatory function for RIPK1 in restricting endogenous, spontaneous ZBP1 activation. Several groups have recently explored how ZBP1 is activated in sterile conditions and proposed that Z-RNA acts as the ligand to activate ZBP1-mediated cell death and inflammation (Devos et al, 2020;Jiao et al, 2020;Kesavardhana et al, 2020;Wang et al, 2020). Understanding this pathway is essential to unlock key mechanisms, perhaps the sensing of Z-NAs, that prime skin inflammation and autoinflammatory diseases and identify specific signaling cascades for therapeutic targeting.…”

“…Understanding this pathway is essential to unlock key mechanisms, perhaps the sensing of Z-NAs, that prime skin inflammation and autoinflammatory diseases and identify specific signaling cascades for therapeutic targeting. Devos et al (2020) and other recent studies have identified that endogenous nucleic acid sensing is critical for ZBP1 activation to induce necroptosis, skin and colon inflammation, and perinatal lethality (Jiao et al, 2020;Kesavardhana et al, 2020;Wang et al, 2020). To understand ZBP1 activation mechanisms, Devos et al (2020) crossed Ripk1 EKO mice with ZBP1 knock-in mice, which contain mutations disrupting the nucleic acid binding of the ZBP1 Zα domains (N46A, Y50A, N122A, Y126A; Maelfait et al, 2017).…”

“…Thus, ZBP1 activation is cell intrinsic under sterile conditions, and endogenous nucleic acids may potentially be the ligands engaging its activation. Other recent studies also have shown that the Zα domains of ZBP1 are critical for triggering skin and bowel inflammation, the perinatal lethality of Ripk1 mRHIM mice, and IAV-induced PANoptosis via the assembly of a PANoptosome, suggesting a role for Z-NA sensing in regulating physiological functions (Table 1; Christgen et al, 2020;Jiao et al, 2020;Kesavardhana et al, 2020;Samir et al, 2020;Wang et al, 2020;Zhang et al, 2020). Under sterile conditions, double-stranded RNAs (dsRNAs) from endogenous retrovirus (ERV) elements bind ZBP1 and are implicated in its activation (Jiao et al, 2020;Wang et al, 2020).…”