ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence of RIPK1

Abstract

Receptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-α, TLR ligands, and IFNs. Genetic ablation of Ripk1 results in perinatal lethality arising from both RIPK3-mediated necroptosis and FADD/caspase-8–driven apoptosis. IFNs are thought to contribute to the lethality of Ripk1-deficient mice by activating inopportune cell death during parturition, but how IFNs activate cell death in the absence of RIPK1 is not understood. In this study, we show that Z-form nucleic acid binding protein 1 (ZBP1; also known as DAI) drives IFN-stimulated cell death in settings of RIPK1 deficiency. IFN-activated Jak/STAT signaling induces robust expression of ZBP1, which complexes with RIPK3 in the absence of RIPK1 to trigger RIPK3-driven pathways of caspase-8–mediated apoptosis and MLKL-driven necroptosis. In vivo, deletion of either Zbp1 or core IFN signaling components prolong viability of Ripk1−/− mice for up to 3 mo beyond parturition. Together, these studies implicate ZBP1 as the dominant activator of IFN-driven RIPK3 activation and perinatal lethality in the absence of RIPK1.

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

“…Firstly, cultured primary RIPK1 keratinocytes, grown in sterile conditions, succumb to IFN-induced necroptosis, which crucially depended on the nucleic acid sensing capability of ZBP1. This is in agreement with earlier studies reporting on the toxicity of IFNs for RIPK1-deficient fibroblasts (Dillon et al, 2014;Kaiser et al, 2014), and which was recently shown to depend on ZBP1 (Ingram et al, 2019;Yang et al, 2019). Secondly, embryos expressing a mutant RIPK1 RHIM develop ZBP1-RIPK3-MLKL driven inflammatory epidermal hyperplasia at embryonic day 18.5, before exposure to microbes at birth (Lin et al, 2016;.…”

OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis

“…This observation suggests that OTULIN may also suppress the pathways that are responsible for the production of IFNs, either indirectly by preventing overall inflammation or by direct control of IFN production. In that context, FADD and RIPK1 have been identified as being implicated in an immune defense pathway against intracellular double-stranded RNA (dsRNA) (Balachandran et al, 2004;Michallet et al, 2008;Rajput et al, 2011;Ingram et al, 2019). Further studies are required to identify the pathway(s) regulated by OTULIN driving type I IFN production.…”

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

“…This observation suggests that OTULIN might also suppress pathways responsible for the production of interferons, either indirectly by preventing overall inflammation, or by direct control of interferon production. In that context, FADD and RIPK1 have been identified as being implicated in an immune defense pathway against intracellular dsRNA (Balachandran et al, 2004; Michallet et al, 2008; Rajput et al, 2011; Ingram et al, 2019). Further studies are required to identify the pathway(s) regulated by OTULIN driving type I interferon production.…”