The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis.
The Pseudokinase MLKL and the Kinase RIPK3 Have Distinct Roles in Autoimmune Disease Caused by Loss of Death-Receptor-Induced Apoptosis.
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DOI：
10.1016/j.immuni.2016.07.016
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发表时间：
2016-09-20
期刊：
影响因子：
32.4
通讯作者：
Strasser, Andreas
中科院分区：
文献类型：
--
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
激酶RIPK 1和RIPK 3以及假激酶MLKL已被鉴定为坏死性凋亡细胞死亡途径的关键调节因子，尽管MLKL在整个动物中的作用尚未确定。在这里，我们已经表明，MLKL缺乏挽救了由Caspase-8或FADD丢失引起的胚胎致死性。Casp 8 −/−Mlkl−/−和Fadd−/−Mlkl−/−小鼠存活且可生育，但迅速发展为严重的淋巴结病、全身性自身免疫性疾病和血小板减少症。与Casp 8 −/− Ripk 3 −/−或Fadd −/− Ripk 3 −/−小鼠相比，Casp 8 −/− Mlkl −/−和Fadd −/−Mlkl−/−小鼠的这些发病率发生更快，严重程度更高。这些结果表明，MLKL是由Caspase-8或FADD缺失引起的胚胎坏死性凋亡的重要效应物。此外，他们表明RIPK 3和/或MLKL可以独立于坏死性凋亡发挥功能。似乎RIPK 3的非坏死性功能有助于当FADD或半胱天冬酶-8介导的细胞凋亡被废除时发生的淋巴结病、自身免疫和过量细胞因子产生。
The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease and thrombocytopenia. These morbidities occurred more rapidly and with increased severity in Casp8−/−Mlkl−/− and Fadd−/−Mlkl−/− mice compared to Casp8−/−Ripk3−/− or Fadd−/−Ripk3−/− mice, respectively. These results demonstrate that MLKL is an essential effector of necroptosis in embryos caused by loss of Caspase-8 or FADD. Furthermore, they suggest that RIPK3 and/or MLKL may exert functions independently of necroptosis. It appears that non-necroptotic functions of RIPK3 contribute to the lymphadenopathy, autoimmunity and excess cytokine production that occur when FADD or caspase-8 mediated apoptosis is abrogated.
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影响因子：
16
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
通讯作者：
Kaiser WJ
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：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
影响因子：
8.8
作者：
Dillon CP;Oberst A;Weinlich R;Janke LJ;Kang TB;Ben-Moshe T;Mak TW;Wallach D;Green DR
通讯作者：
Green DR