RESUMO
The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)1. In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutières syndrome (AGS)2. In mice, complete loss of ADAR1 activity is embryonically lethal3-6, and mutations similar to those found in patients with AGS cause autoinflammation7-12. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR3,7-10,13,14. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Zα domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function.
Assuntos
Adenosina Desaminase , Inflamação , Proteínas de Ligação a RNA , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Adenosina/metabolismo , Adenosina Desaminase/química , Adenosina Desaminase/deficiência , Adenosina Desaminase/metabolismo , Animais , Apoptose , Doenças Autoimunes do Sistema Nervoso , Caspase 8/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/prevenção & controle , Inosina/metabolismo , Intestinos/patologia , Camundongos , Necroptose , Malformações do Sistema Nervoso , Edição de RNA , RNA de Cadeia Dupla , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Pele/patologiaRESUMO
Cell death forms an essential component of the antiviral immune response. Viral infection elicits different forms of host cell death, including the lytic and inflammatory cell death modes necroptosis or pyroptosis. The induction of both types of cell death not only eliminates virus-infected cells but also contributes to the development of innate and adaptive immunity through the release of inflammatory mediators. The importance of necroptosis and pyroptosis in host defence is evident from the numerous viral evasion mechanisms that suppress these cell death pathways. Here, we review the emerging principles by which viruses antagonise host cell necroptosis and pyroptosis to promote their spread and block host immunity.
