Open AccessHsp90β interacts with MDM2 to suppress p53‐dependent senescence during skeletal muscle regeneration
Author(s) -
He Min Yi,
Xu Shui Bo,
Qu Zi Hao,
Guo Yue Mei,
Liu Xiao Ceng,
Cong Xiao Xia,
Wang Jian Feng,
Low Boon Chuan,
Li Li,
Wu Qiang,
Lin Peng,
Yan Shi Gui,
Bao Zhang,
Zhou Yi Ting,
Zheng Li Ling
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13003
Subject(s) - biology , senescence , hsp90 , gene knockdown , regeneration (biology) , microbiology and biotechnology , downregulation and upregulation , ubiquitin ligase , myocyte , mdm2 , skeletal muscle , heat shock protein , ubiquitin , cell culture , genetics , anatomy , gene
Abstract 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 Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA‐seq analysis disclosed a transcriptional elevation of p21 in Hsp90β‐depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53‐dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild‐type p53 and modulated its degradation via a proteasome‐dependent manner. Moreover, Hsp90β 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 Hsp90β 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 Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.