ADAR1 mutation causes ZBP1-dependent immunopathology

Hubbard, Nicholas; Ames, Joshua; Maurano, Megan M.; Chu, Lan H.; Somfleth, Kim; Gokhale, Nandan S.; Werner, Margo; Snyder, Jessica M.; Lichauco, Katrina; Savan, Ram; Stetson, Daniel B.; Oberst, Andrew

doi:10.1038/s41586-022-04896-7

Cited by 121 publications

(117 citation statements)

References 45 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…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 ]. ZBP1 plays a dual role in mice with impaired ADAR1 function.…”

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

“…ZBP1 plays a dual role in mice with impaired ADAR1 function. 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 ].…”

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

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

Hao

Yang

et al. 2022

IJMS

View full text Add to dashboard Cite

Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed double-helix Z-nucleic acid (includes Z-DNA and Z-RNA) and subsequent signaling transduction depends on the interaction between ZBP1 and its adapter proteins, such as TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3. ZBP1 activated innate immunity, including type-I interferon (IFN-I) response and NF-κB signaling, constitutes an important line of defense against pathogenic infection. In addition, ZBP1-mediated PANoptosis is a double-edged sword in anti-infection, auto-inflammatory diseases, and tumor immunity. ZBP1-mediated PANoptosis is beneficial for eliminating infected cells and tumor cells, but abnormal or excessive PANoptosis can lead to a strong inflammatory response that is harmful to the host. Thus, pathogens and host have each developed multiplex tactics targeting ZBP1 signaling to maintain strong virulence or immune homeostasis. In this paper, we reviewed the mechanisms of ZBP1 signaling, the effects of ZBP1 signaling on host immunity and pathogen infection, and various antagonistic strategies of host and pathogen against ZBP1. We also discuss existent gaps regarding ZBP1 signaling and forecast potential directions for future research.

show abstract

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

Section: Zbp1 Signaling In Auto-inflammatory Diseasesmentioning

confidence: 99%

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

Hao

Yang

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…ZBP-1 is the only other mammalian Zα domain containing protein and has been linked to aspects of ADAR1 biology (Zhang et al, 2022). It is not at present clear how this reconciles with the prior model where activation of PKR and the integrated stress response was proposed as the primary driver of the phenotypes in their Adar1 P195A/− model (Hubbard et al ., 2022; Maurano et al ., 2021). We see complete rescue of the Adar1 P195A/− and Adar1 P195A/E861A mice by loss of MDA5 with a full suppression of ISG expression to baseline levels in vivo , consistent with a model where MDA5 is the primary, and initiating, sensor of unedited self dsRNA.…”

Section: Discussionmentioning

confidence: 71%

“…ZBP-1 is the only other mammalian Za domain containing protein and has been linked to aspects of ADAR1 biology (Zhang et al, 2022). It is not at present clear how this reconciles with the prior model where activation of PKR and the integrated stress response was proposed as the primary driver of the phenotypes in their Adar1 P195A/model (Hubbard et al, 2022;Maurano et al, 2021). We see complete rescue of the Adar1 B) Survival analysis of mice of the indicated genotypes (all Ifih1 -/-); number as indicated for each genotype.…”

Section: Discussionmentioning

confidence: 81%

“…We also assessed levels of phospho-eIF2a, a marker of PKR activation, in the kidney of the runted Adar1 P195A/− animals and did not see any difference to normal sized Adar1 P195A/− and control animals (Supp Fig 3D). Most recently it has been proposed by the same group that the pathology of the Adar1 P195A/− animals is due to activation of an alternative protein, ZBP-1 (Hubbard et al, 2022). ZBP-1 is the only other mammalian Zα domain containing protein and has been linked to aspects of ADAR1 biology (Zhang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The most common human ADAR1p150 Zα domain mutation P193A is well tolerated in mice and does not activate the integrated stress response pathway

Liang

Taylor

Goradia

et al. 2022

Preprint

View full text Add to dashboard Cite

ADAR1 mediated A-to-I RNA editing is a self/non-self discrimination mechanism for cellular double stranded RNAs. ADAR mutations are one cause of Aicardi-Goutieres Syndrome, an inherited paediatric encephalopathy, broadly classed as a Type I interferonopathy. The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform specific Zα domain. We report the development of an independent murine P195A knock-in mouse, homologous to the human P193A mutation. The Adar1P195A/P195A mice are largely normal and the mutation is well tolerated. Contrasting with previous reports when the P195A mutation was compounded with an ADAR1 null allele, the majority of mice have only a modest reduction in weaning weight and survived long-term. Severe runting and shortened survival of Adar1P195A/- animals are dependent on the parental genotype. The P195A mutation is well tolerated in vivo and the loss of MDA5 is sufficient to completely rescue the Adar1P195A/- mice.

show abstract

Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

Herbert

2022

BioEssays

View full text Add to dashboard Cite

Alternative non‐B‐DNA conformations formed under physiological conditions by sequences called flipons include left‐handed Z‐DNA, three‐stranded triplexes, and four‐stranded i‐motifs and quadruplexes. These conformations accumulate and release energy to enable the local assembly of cellular machines in a context specific manner. In these transactions, nucleosomes store power, serving like rechargeable batteries, while flipons smooth energy flows from source to sink by acting as capacitors or resistors. Here, I review the known biological roles for flipons. I present recent and unequivocal findings showing how innate immune responses are regulated by Z‐flipons that identify endogenous RNAs as self. Evidence is also presented supporting important roles for other flipon classes. In these examples, the dynamic exchange of energy between flipons and nucleosomes enables rapid switching of genetic programs without altering flipon sequence. The increased phenotypic diversity enabled by flipons drives their natural selection, with adaptations evolving faster than is possible by codon mutation alone.

show abstract

ADAR1 mutation causes ZBP1-dependent immunopathology

Cited by 121 publications

References 45 publications

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

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

The most common human ADAR1p150 Zα domain mutation P193A is well tolerated in mice and does not activate the integrated stress response pathway

Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

Contact Info

Product

Resources

About