Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration
Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration
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Hsp90 beta 与 MDM2 相互作用抑制骨骼肌再生过程中 p53 依赖性衰老
DOI：
10.1111/acel.13003
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发表时间：
2019-07-17
期刊：
影响因子：
7.8
通讯作者：
Zheng, Li Ling
中科院分区：
文献类型：
--
作者：
He, Min Yi;Xu, Shui Bo;Zheng, Li Ling
细胞衰老在胚胎发育和组织再生过程中起着有益和有害的作用，但其潜在机制仍不清楚。最近的研究揭示了热休克蛋白在调节肌肉再生和稳态中的新作用。在这里，我们发现，热休克蛋白90 β，而不是热休克蛋白90 α亚型，在肌肉再生过程中显着上调。RNA-seq分析揭示了在Hsp 90 β耗尽的成肌细胞中p21的转录升高，这是由于p53的上调。此外，敲低成肌细胞中的Hsp 90 β导致p53依赖性细胞衰老。与Hsp 90与癌症中的突变型p53相互作用并保护突变型p53的观点相反，Hsp 90 β优先结合野生型p53并通过蛋白酶体依赖性方式调节其降解。此外，Hsp 90 β与p53的主要E3连接酶MDM 2相互作用，以调节p53的稳定性。与这些体外研究一致，在老年小鼠肌肉中，p53-p21轴的表达水平与Hsp 90 β呈负相关。一致地，在临床试验中，施用Hsp 90抑制剂17-AAG通过增强损伤诱导的体内衰老而损害肌肉再生。综上所述，我们的发现揭示了Hsp 90 β在调节p53稳定性以抑制体外和体内衰老中的先前未被认识的作用。
Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat-shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90 beta, but not Hsp90 alpha isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90 beta-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90 beta in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90 beta preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90 beta interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90 beta in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90 beta in regulating p53 stability to suppress senescence both in vitro and in vivo.