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Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis

机译：Hsp90调节MLKL的稳定性，是TNF诱导的坏死性坏死病所必需的

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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.
机译：假激酶混合谱系激酶域样蛋白（MLKL）是肿瘤坏死因子（TNF）诱导的坏死病的关键成分，在坏死病的执行中起着至关重要的作用。但是，尚未完全了解控制MLKL活性的机制。在这里，我们确定分子伴侣Hsp90为新型的MLKL相互作用蛋白。我们显示Hsp90与MLKL相关联，并且是MLKL稳定性所必需的。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，从而导致它们通过蛋白酶体途径降解。此外，我们发现TNF刺激的坏死体组装需要Hsp90。 Hsp90功能的破坏阻止了坏死体的形成，并大大降低了MLKL的磷酸化并抑制了TNF引起的坏死性肾病。与Hsp90在坏死性硬化中的积极作用相一致，Hsp90的共表达增加MLKL寡聚化和质膜易位，并增强MLKL介导的坏死性硬化。我们的发现表明，有效的坏死反应需要功能性Hsp90。

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