Chemical screening identifies ATM as a target for alleviating senescence
Chemical screening identifies ATM as a target for alleviating senescence
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DOI：
10.1038/nchembio.2342
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发表时间：
2017-06-01
影响因子：
14.8
通讯作者：
Park, Sang Chul
中科院分区：
文献类型：
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作者：
Kang, Hyun Tae;Park, Joon Tae;Park, Sang Chul
衰老被定义为不可逆转的细胞周期停滞，是衰老和老年性疾病的主要驱动力。在这里，我们进行了高通量筛选，以确定延缓衰老的化合物，并确定共济失调毛细血管扩张突变(ATM)抑制剂KU-60019为有效药物。为了阐明ATM在衰老中的作用机制，我们进行了酵母双杂交筛选，发现ATM与空泡ATPase V-1亚基ATP6V1E1和ATP6V1G1相互作用。具体地说，ATM通过直接磷酸化ATP6V1G1来减少E-G二聚化。ATM活性的减弱恢复了二聚化，从而促进了V-1和V-0结构域的组装，并伴随着溶酶体的再酸化。反过来，这种再酸化导致溶酶体/自噬系统的功能恢复，并与线粒体功能恢复和代谢重新编程相结合。总之，我们的数据揭示了一种新的衰老机制，通过这种机制，溶酶体-线粒体轴的功能受到ATM活性微调的调节。
Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V-1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V-1 and V-0 domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.