Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, The University of California, Berkeley, Berkeley, California, USA.
Aging Cell. 2023 Jan;22(1):e13742. doi: 10.1111/acel.13742. Epub 2022 Nov 20.
The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energyconsuming network with dynamic properties to shape the structure and function of the cell. Proper actin function is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis. Deterioration of these processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well-understood. Here, we performed a multipronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo Caenorhabditis elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator of actin function and longevity. Overexpression of bet-1 preserves actin function at late age and promotes life span and healthspan in C. elegans. These beneficial effects are mediated through actin preservation by the transcriptional regulator function of BET-1. Together, our discovery assigns a key role for BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
肌动蛋白细胞骨架是一种蛋白质的三维支架，是一个具有动态特性的调节、耗能网络，能够塑造细胞的结构和功能。适当的肌动蛋白功能是许多细胞途径所必需的，包括细胞分裂、自噬、伴侣蛋白功能、内吞作用和外排作用。这些过程的恶化发生在衰老和暴露于应激时，部分原因是肌动蛋白细胞骨架的破坏。然而，涉及细胞骨架形态和功能保存的调节机制尚不清楚。在这里，我们进行了一种多管齐下的、跨生物体的筛选，将人类成纤维细胞中的全基因组 CRISPR-Cas9 筛选与体内秀丽隐杆线虫的合成致死性筛选相结合。我们发现溴结构域蛋白 BET-1 是肌动蛋白功能和寿命的关键调节剂。bet-1 的过表达在老年时保持肌动蛋白功能，并促进秀丽隐杆线虫的寿命和健康寿命。这些有益的效果是通过 BET-1 的转录调节功能介导的肌动蛋白保存来实现的。总之，我们的发现赋予了 BET-1 在细胞骨架健康中的关键作用，突出了促进细胞骨架动态平衡的调节细胞网络。
