Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, 50931, Cologne, Germany.
Cell Mol Life Sci. 2021 Jul;78(13):5275-5301. doi: 10.1007/s00018-021-03843-5. Epub 2021 May 23.
For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.
很长一段时间以来，PLS3（也称为 T-肌动蛋白或 fimbrin）一直被认为是一种相当不起眼的蛋白质，参与 F-肌动蛋白的结合和束状。然而，近年来，大量的发现使 PLS3 成为一种涉及许多细胞过程、信号通路和疾病的高度有趣的蛋白质。PLS3 位于 X 染色体上，但表现出性别特异性、个体间和组织特异性表达变异性，指向偏性 X 失活。PLS3 在所有实体组织中表达，但通常不在造血细胞中表达。当逃避 X 失活时，PLS3 会引发多种不同类型的癌症。升高的 PLS3 水平被认为是癌症的预后生物标志物，也是对治疗产生耐药性的原因。当它在人类和小鼠中被敲除或突变时，会导致骨质疏松症和骨折；它是唯一一种参与肌动蛋白动力学导致骨质疏松症的蛋白质。相反，当 PLS3 上调时，它在脊髓性肌萎缩症（SMA）中作为一种高度保护性的 SMN 非依赖性修饰物发挥作用。在这里，它似乎通过恢复因 SMN 水平降低而受损的内吞作用和紊乱的钙稳态来对抗 F-肌动蛋白水平的降低。相比之下，PLS3 在野生型水平上的上调可能会导致骨关节炎。这强调了我们细胞中 PLS3 的数量必须精确平衡；过多和过少都可能有害。肌动蛋白动力学，由 PLS3 等调节，在包括内吞作用、细胞迁移、轴突生长、神经传递、翻译和其他许多细胞过程中都至关重要。此外，PLS3 水平还影响着不同细菌、真菌感染和其他病原体的感染。
