PKR and the Integrated Stress Response drive immunopathology caused by ADAR1 mutation

Maurano, Megan M.; Snyder, Jessica M.; Connelly, Caitlin; Henao‐Mejia, Jorge; Sidrauski, Carmela; Stetson, Daniel B.

doi:10.1101/2020.11.30.405498

Cited by 3 publications

(5 citation statements)

References 67 publications

(93 reference statements)

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“…In addition, this study revealed that the embryonic lethality found in Adar1 E861A/E861A mice can be rescued by the sole expression of ADAR1 p150. Of note, we and other groups have recently reported that a point mutation in the ADAR1 p150-specific Zα domain induces the upregulated expression of ISGs in multiple organs, including the brain [53][54][55][56]. These lines of evidence indicate that ADAR1 p150-mediated RNA editing is essential to escape MDA5-sensing, even in brain where a subtle amount of ADAR1 p150 is expressed.…”

Section: Plos Geneticsmentioning

confidence: 77%

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

et al. 2021

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Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi–Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing–mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110–specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150–mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150–mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150–specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain.

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Section: Plos Geneticsmentioning

confidence: 77%

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

et al. 2021

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“…Subsequent experiments demonstrated that the mouse equivalent to the P193A variant recapitulated the human Zα mendelian phenotype [36]. Three other recently generated mouse models using different loss of function Zα residues variants also were associated with a type I interferon signature [37][38][39].…”

Section: Adar1 and Human Diseasementioning

confidence: 99%

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Herbert

2021

PLoS Genet

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Double-stranded RNA (dsRNA) is produced both by virus and host. Its recognition by the melanoma differentiation–associated gene 5 (MDA5) initiates type I interferon responses. How can a host distinguish self-transcripts from nonself to ensure that responses are targeted correctly? Here, I discuss a role for MDA5 helicase in inducing Z-RNA formation by Alu inverted repeat (AIR) elements. These retroelements have highly conserved sequences that favor Z-formation, creating a site for the dsRNA-specific deaminase enzyme ADAR1 to dock. The subsequent editing destabilizes the dsRNA, ending further interaction with MDA5 and terminating innate immune responses directed against self. By enabling self-recognition, Alu retrotransposons, once invaders, now are genetic elements that keep immune responses in check. I also discuss the possible but less characterized roles of the other helicases in modulating innate immune responses, focusing on DExH-box helicase 9 (DHX9) and Mov10 RISC complex RNA helicase (MOV10). DHX9 and MOV10 function differently from MDA5, but still use nucleic acid structure, rather than nucleotide sequence, to define self. Those genetic elements encoding the alternative conformations involved, referred to as flipons, enable helicases to dynamically shape a cell’s repertoire of responses. In the case of MDA5, Alu flipons switch off the dsRNA-dependent responses against self. I suggest a number of genetic systems in which to study interactions between flipons and helicases further.

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“…Postnatal mortality in these mutant mice could be prevented by feeding an ISR inhibitor that prevented translational arrest via eIF2α. Similar PKR-dependent ISR transcript upregulation in response to IFNβ was seen in an analogous, CRISPR/Cas9-based A549 cell model and overall suggests PKR is a downstream effector of the MDA5 and LGP2-induced IFN response ( 86 ). This hypothesis is further supported by a separate study investigating key mediators of anti-tumour immunity in ADAR1-null B16 cells, which naturally secrete IFNβ and undergo growth arrest ( 85 ).…”

Section: Pkrmentioning

confidence: 68%

“…Endogenous nuclear-derived dsRNA can accumulate and activate PKR and its downstream targets in response to different stressors and conditions. Two recently published examples are ADAR1 dysfunction and exposure to phosphorothioate-modified antisense oligos (ASOs), which induce PKR-dependent eIF2α phosphorylation ( 84 – 86 ). The postnatally lethal phenotype and ISR and ISG expression signature of Adar1 P195A/p150- mice, which lack the catalytically active, IFN-inducible Adar1 isoform p150, has previously been described as MDA5-dependent ( 30 ).…”

Section: Pkrmentioning

confidence: 99%

“…A recent publication by Maurano et al. ( 86 ) showed that LGP2, IFNAR1 and PKR are also essential factors mediating postnatal lethality and induction of ISR genes in Adar1 P195A/p150- mice, while PKR was dispensable for ISG expression. Postnatal mortality in these mutant mice could be prevented by feeding an ISR inhibitor that prevented translational arrest via eIF2α.…”

Section: Pkrmentioning

confidence: 99%

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Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis

Straub

Sampaio

2023

Front. Immunol.

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Early detection of infection is a central and critical component of our innate immune system. Mammalian cells have developed specialized receptors that detect RNA with unusual structures or of foreign origin – a hallmark of many virus infections. Activation of these receptors induces inflammatory responses and an antiviral state. However, it is increasingly appreciated that these RNA sensors can also be activated in the absence of infection, and that this ‘self-activation’ can be pathogenic and promote disease. Here, we review recent discoveries in sterile activation of the cytosolic innate immune receptors that bind RNA. We focus on new aspects of endogenous ligand recognition uncovered in these studies, and their roles in disease pathogenesis.

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PKR and the Integrated Stress Response drive immunopathology caused by ADAR1 mutation

Cited by 3 publications

References 67 publications

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain

To “Z” or not to “Z”: Z-RNA, self-recognition, and the MDA5 helicase

Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis

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