期刊
AGING CELL
卷 20, 期 6, 页码 -出版社
WILEY
DOI: 10.1111/acel.13370
关键词
ageing; mTOR; PC4; protein synthesis; proteostasis
资金
- University Innovation Team Building Program of Chongqing [CXTDG201602020]
- National Key Research and Development Program [2016YFC1000805]
- National Natural Science Foundation of China [82030056]
- Intramural Research Project Grants [AWS17J007, 2018-JCJQ-ZQ-001]
The study found that PC4 is accumulated and activated during ageing, causing accelerated ageing by disrupting proteostasis. PC4 interacts with Sin3-HDAC complex, leading to mTOR signaling activation, excessive protein synthesis, ultimately resulting in impaired proteostasis and accelerated ageing.
Research on ageing-associated genes is important for investigating ageing and anti-ageing strategies. Here, we firstly reported that the human positive cofactor 4 (PC4), a multifunctional and highly conserved nucleoprotein, is accumulated and activated during ageing and causes global accelerated ageing process by disrupting proteostasis. Mechanistically, PC4 interacts with Sin3-HDAC complex and inhibits its deacetylated activity, leads to hyper-acetylation of the histones at the promoters of mTOR-related genes and causes mTOR signalling activation. Accordingly, mTOR activation causes excessive protein synthesis, resulting in impaired proteostasis and accelerated senescence. These results reveal a new biological function of PC4 in vivo, recognizes PC4 as a new ageing-associated gene and provides a genetically engineered mouse model to simulate natural ageing. More importantly, our findings also indicate that PC4 is involved in histone acetylation and serves as a potential target to improve proteostasis and delay ageing.
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