Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell. 2013 Aug 29;154(5):971-982. doi: 10.1016/j.cell.2013.07.037.
Intracellular proteins with long lifespans have recently been linked to age-dependent defects, ranging from decreased fertility to the functional decline of neurons. Why long-lived proteins exist in metabolically active cellular environments and how they are maintained over time remains poorly understood. Here, we provide a system-wide identification of proteins with exceptional lifespans in the rat brain. These proteins are inefficiently replenished despite being translated robustly throughout adulthood. Using nucleoporins as a paradigm for long-term protein persistence, we found that nuclear pore complexes (NPCs) are maintained over a cell's life through slow but finite exchange of even its most stable subcomplexes. This maintenance is limited, however, as some nucleoporin levels decrease during aging, providing a rationale for the previously observed age-dependent deterioration of NPC function. Our identification of a long-lived proteome reveals cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. PAPERCLIP:
最近，具有长寿命的细胞内蛋白质与年龄相关的缺陷有关，这些缺陷的范围从生育能力下降到神经元功能衰退。为什么长寿命的蛋白质存在于代谢活跃的细胞环境中，以及它们如何随着时间的推移而保持，这仍然知之甚少。在这里，我们提供了一种在大鼠大脑中进行全系统鉴定具有超长寿命的蛋白质的方法。这些蛋白质尽管在整个成年期都被强烈地翻译，但却不能有效地补充。我们以核孔蛋白为例，研究了长期蛋白质持久性，发现核孔复合物（NPC）通过即使是最稳定的亚复合物的缓慢但有限的交换来维持细胞的寿命。然而，这种维持是有限的，因为随着年龄的增长，一些核孔蛋白的水平会下降，这为之前观察到的 NPC 功能随年龄下降提供了合理的解释。我们对长寿命蛋白质组的鉴定揭示了细胞成分容易受到损伤积累的影响，将长期蛋白质持久性与细胞衰老过程联系起来。
