School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
School of Biological Sciences, Seoul National University, Seoul 08826, South Korea; Center for RNA Research, Institute of Basic Science, Seoul 08826, South Korea.
Dev Cell. 2021 May 17;56(10):1512-1525.e7. doi: 10.1016/j.devcel.2021.04.008. Epub 2021 Apr 28.
Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes.
细胞衰老作为一种与衰老相关的复杂应激反应，受到广泛关注。自噬可以抑制衰老，但对于完全衰老却是必需的，这有违常理。尽管自噬在抗衰老方面的作用已被充分描述，但自噬在衰老建立中的作用及其潜在机制仍知之甚少。在这里，我们展示了多种调控成分的选择性自噬协调衰老的稳态。我们将自噬成分的蛋白质组学分析与蛋白质稳定性分析相结合，鉴定出参与多种与衰老相关过程的自噬底物蛋白。KEAP1 的选择性自噬促进了衰老过程中的氧化还原平衡。此外，选择性自噬限制了翻译机制成分，以减轻与衰老相关的蛋白毒性应激。最后，TNIP1 的选择性自噬增强了与衰老相关的炎症。这些选择性自噬网络似乎在人类骨关节炎的体内衰老过程中发挥作用。我们的数据强调了自噬在衰老应激支持网络中的管家作用，这是通过调节蛋白质稳定性实现的，并揭示了两个重要的与年龄相关的过程之间相互交织的关系。
