Activated MLKL attenuates autophagy following its translocation to intracellular membranes
Activated MLKL attenuates autophagy following its translocation to intracellular membranes
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DOI：
10.1242/jcs.220996
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发表时间：
2019-03-01
影响因子：
4
通讯作者：
Lindqvist, Lisa M.
中科院分区：
文献类型：
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作者：
Frank, Daniel;Vaux, David L.;Lindqvist, Lisa M.
坏死性凋亡是由假激酶混合谱系激酶结构域样蛋白（MLKL）介导的程序性细胞死亡的炎性形式。通过受体相互作用蛋白激酶-3（RIPK 3）磷酸化后，MLKL寡聚化，并易位至质膜并破坏质膜，从而引起坏死性细胞溶解。在本文中，我们表明，小鼠皮肤成纤维细胞（MDF）和HT-29人结直肠癌细胞中坏死性凋亡的激活导致自噬标志物脂化LC 3B（也称为MAP 1 LC 3B）以MLKL依赖性方式积累。出乎意料的是，坏死性凋亡诱导的脂化LC 3B增加是由于自噬通量的抑制，而不是自噬的激活。MLKL对自噬的抑制与自噬体和/或自溶酶体功能的降低相关，并且需要活化的MLKL与细胞内膜的结合。总的来说，我们的研究结果揭示了MLKL假激酶的另一个作用，即在坏死性凋亡过程中抑制自噬。
Necroptosis is an inflammatory form of programmed cell death mediated by the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Upon phosphorylation by receptor-interacting protein kinase-3 (RIPK3), MLKL oligomerizes, and translocates to and disrupts the plasma membrane, thereby causing necroptotic cell lysis. Herein, we show that activation of necroptosis in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells results in accumulation of the autophagic marker, lipidated LC3B (also known as MAP1LC3B), in an MLKL-dependent manner. Unexpectedly, the necroptosis-induced increase in lipidated LC3B was due to inhibition of autophagic flux, not the activation of autophagy. Inhibition of autophagy by MLKL correlated with a decrease in autophagosome and/or autolysosome function, and required the association of activated MLKL with intracellular membranes. Collectively, our findings uncover an additional role for the MLKL pseudokinase, namely to inhibit autophagy during necroptosis.