Inhibition of Protein Degradation Induces Apoptosis through a Microtubule-Associated Protein 1 Light Chain 3-Mediated Activation of Caspase-8 at Intracellular Membranes
Inhibition of Protein Degradation Induces Apoptosis through a Microtubule-Associated Protein 1 Light Chain 3-Mediated Activation of Caspase-8 at Intracellular Membranes
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DOI：
10.1128/mcb.05460-11
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发表时间：
2011-08-01
影响因子：
5.3
通讯作者：
Zong, Wei-Xing
中科院分区：
文献类型：
--
作者：
Pan, Ji-An;Ullman, Erica;Zong, Wei-Xing
受损或错误折叠的蛋白质的积累，如果未解决，可能导致细胞内的有害后果，称为蛋白毒性。由于癌细胞通常表现出升高的蛋白质合成和副产物处置，因此抑制蛋白质降解途径是癌症治疗的新兴方法。然而，蛋白毒性的分子机制仍然很不清楚。我们在这里表明，抑制蛋白酶体降解的结果在增加寡聚化和激活的caspase-8的细胞内膜的胞质侧。这种增强的caspase-8寡聚化和活化通过其与泛素结合蛋白SQSTM 1/p62和微管相关蛋白轻链3（LC 3）的相互作用而促进，所述蛋白轻链3在细胞内膜处响应于蛋白毒性应激而富集。通过shRNA沉默LC 3，或膜定位缺陷或p62相互作用的LC 3突变体不能诱导caspase-8活化和凋亡。我们的研究结果揭示了一种以前未知的机制，通过这种机制，蛋白质稳态的破坏诱导caspase-8寡聚化，激活和凋亡。
The accumulation of damaged or misfolded proteins, if unresolved, can lead to a detrimental consequence within cells termed proteotoxicity. Since cancerous cells often display elevated protein synthesis and by-product disposal, inhibition of the protein degradation pathways is an emerging approach for cancer therapy. However, the molecular mechanism underlying proteotoxicity remains largely unclear. We show here that inhibition of proteasomal degradation results in an increased oligomerization and activation of caspase-8 on the cytosolic side of intracellular membranes. This enhanced caspase-8 oligomerization and activation are promoted through its interaction with the ubiquitin-binding protein SQSTM1/p62 and the microtubule-associated protein light chain 3 (LC3), which are enriched at intracellular membranes in response to proteo-toxic stress. Silencing LC3 by shRNA, or the LC3 mutants defective in membrane localization or p62 interaction fail to induce caspase-8 activation and apoptosis. Our results unveiled a previously unknown mechanism through which disruption of protein homeostasis induces caspase-8 oligomerization, activation, and apoptosis.