ADAR1 averts fatal type I interferon induction by ZBP1

Abstract

Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi–Goutières syndrome and bilateral striatal necrosis1–3. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA4,5. Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans2,3 and mice6–8; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains9, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (Adar1mZα/– mice). Adar1mZα/– mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1mZα/– mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations.

A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

“…2e). Our finding appears to contradict with findings that suggest the importance of Zα domain of ADAR1 in human patients 35,46 and animal models [47][48][49][50][51][52][53][54] . The discrepancy may suggest that overexpression of p150 in our cellular assays compensate the effect of the Zα domain.…”

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

“…ADAR1 is responsible for the adenosine to inosine (A-to-I) edits of ERV-derived dsRNA and represses abnormal immune responses activated by ERVs [ 156 , 157 , 158 , 159 ]. Deletion of ADAR1 or mutant of the Zα domain of ADAR1 causes the accumulation of ERV-derived dsRNA and spontaneous activation of ZBP1 [ 160 , 161 ]. The abnormal activation of ZBP1 causes embryonic lethality, intestinal cell death and skin inflammation similar to RIPK1 −/− or RIPK1 mR/mR mice [ 162 , 163 ].…”

“…On the one hand, ZBP1 induces RIPK3-mediated necroptosis and CASP-8-mediated apoptosis which is MAVS-independent [ 162 , 163 ]. On the other hand, ZBP1 promotes the RIPK1- and RIPK3-independent, but MAVS-dependent IFN-I responses and stimulates interferonopathies [ 160 ].…”

The role of RHIM in necroptosis

“…Therein, the authors were able to induce necroptosis and apoptosis in vitro and re-sensitize tumor cells to treatment with checkpoint inhibitors in vivo [39]. In line with these observations, defects in the function of the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) induces ZBP1 activation via the accumulation of endogenous double-stranded RNA which, led to pathological cell death and autoinflammation [39,[84][85][86]. Other newly discovered non-canonical activators of RIPK3-mediated cell death are heat stress and osmotic stress [87,88].…”