ADAR1 mutation causes ZBP1-dependent immunopathology.
ADAR1 mutation causes ZBP1-dependent immunopathology.
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ADAR1突变引起zbp1依赖性免疫病理。
DOI：
10.1038/s41586-022-04896-7
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发表时间：
2022-07
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
RNA编辑酶ADAR 1对于抑制先天免疫激活和由自身RNA异常识别引起的病理至关重要，它通过破坏内源性双链RNA种类的双链体结构来发挥这一作用。ADAR 1的Z-核酸结合结构域（ZBD）中的点突变与严重的自身炎症性疾病相关。ZBP 1是唯一一种含有ZBD的哺乳动物蛋白质，其激活可以通过激酶RIPK 1和RIPK 3以及蛋白酶caspase-8触发细胞死亡和转录反应。在这里，我们表明ADAR 1 ZBD突变引起的病理是由ZBP 1激活驱动的。我们发现ZBP 1的消融完全挽救了ADAR 1突变引起的明显病理，而没有完全逆转由该突变引起的潜在炎症程序。虽然RIPK 3的缺失部分表型模仿了ZBP 1消融的保护作用，但caspase-8和RIPK 3或caspase-8和MLKL的组合缺失出乎意料地加剧了ADAR 1突变的致病作用。这些发现表明，ADAR 1是无菌ZBP 1激活的负调节因子，并且ZBP 1依赖性信号传导是ADAR 1突变引起的自身炎症病理的基础。
The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without fully reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.
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影响因子：
30.3
作者：
Nogusa S;Thapa RJ;Dillon CP;Liedmann S;Oguin TH 3rd;Ingram JP;Rodriguez DA;Kosoff R;Sharma S;Sturm O;Verbist K;Gough PJ;Bertin J;Hartmann BM;Sealfon SC;Kaiser WJ;Mocarski ES;López CB;Thomas PG;Oberst A;Green DR;Balachandran S
通讯作者：
Balachandran S
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
32.4
作者：
Alvarez-Diaz, Silvia;Dillon, Christopher P.;Lalaoui, Najoua;Tanzer, Maria C.;Rodriguez, Diego A.;Lin, Ann;Lebois, Marion;Hakem, Razq;Josefsson, Emma C.;O'Reilly, Lorraine A.;Silke, John;Alexander, Warren S.;Green, Douglas R.;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
64.8
作者：
Lin J;Kumari S;Kim C;Van TM;Wachsmuth L;Polykratis A;Pasparakis M
通讯作者：
Pasparakis M