Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.
Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.
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Hsp90 调节 MLKL 的稳定性，并且是 TNF 诱导的坏死性凋亡所必需的。
DOI：
10.1038/cddis.2015.390
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发表时间：
2016-02-11
影响因子：
9
通讯作者：
Zhang SQ
中科院分区：
文献类型：
--
作者：
Zhao XM;Chen Z;Zhao JB;Zhang PP;Pu YF;Jiang SH;Hou JJ;Cui YM;Jia XL;Zhang SQ
假激酶混合谱系激酶结构域样蛋白（MLKL）是肿瘤坏死因子（TNF）诱导的坏死性凋亡的关键组分，在坏死性凋亡的执行中起着至关重要的作用。然而，控制MLKL活性的机制尚未完全了解。在这里，我们确定的分子伴侣Hsp90作为一种新的MLKL相互作用蛋白。我们表明Hsp90与MLKL相关，并且是MLKL稳定所需的。此外，我们发现Hsp90还调节上游RIP3激酶的稳定性。用17AAG抑制剂干扰Hsp90功能会使MLKL和RIP3不稳定，导致其通过蛋白酶体途径降解。此外，我们发现，热休克蛋白90所需的TNF刺激的坏死体组装。Hsp90功能的破坏防止坏死体形成，并强烈降低MLKL磷酸化和抑制TNF诱导的坏死性凋亡。与Hsp90在坏死性凋亡中的积极作用一致，Hsp90的共表达增加MLKL寡聚化和质膜易位，并增强MLKL介导的坏死性凋亡。我们的研究结果表明，一个有效的坏死反应需要一个功能性热休克蛋白90。
The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as a novel MLKL-interacting protein. We show that Hsp90 associates with MLKL and is required for MLKL stability. Moreover, we find that Hsp90 also regulates the stability of the upstream RIP3 kinase. Interference with Hsp90 function with the 17AAG inhibitor destabilizes MLKL and RIP3, resulting in their degradation by the proteasome pathway. Furthermore, we find that Hsp90 is required for TNF-stimulated necrosome assembly. Disruption of Hsp90 function prevents necrosome formation and strongly reduces MLKL phosphorylation and inhibits TNF-induced necroptosis. Consistent with a positive role of Hsp90 in necroptosis, coexpression of Hsp90 increases MLKL oligomerization and plasma membrane translocation and enhances MLKL-mediated necroptosis. Our findings demonstrate that an efficient necrotic response requires a functional Hsp90.