Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, A-1030 Vienna, Austria.
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, A-1030 Vienna, Austria
Genes Dev. 2015 Feb 1;29(3):225-37. doi: 10.1101/gad.255968.114.
The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a "mechanostat" that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced "inside-out signaling" through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues.
中间丝蛋白 A 型和 B 型核纤层蛋白形成紧邻内核膜的核层支架。B 型核纤层蛋白赋予核弹性，而 A 型核纤层蛋白赋予核粘性和刚性。核纤层蛋白还参与染色质调控和各种影响基因表达的信号通路。核纤层蛋白的力学作用及其在基因调控中的功能通常被视为独立的活动，但最近的发现表明，这些不同功能的高度交联和相互依存的调节，特别是在机械信号转导中。在这个新出现的概念中，核纤层蛋白充当“机械感受器”，从外部感知力，并通过加强细胞骨架和细胞外基质来响应张力。A 型核纤层蛋白、核纤层蛋白 B（emerin）和核骨架与细胞骨架连接物（LINC）复合物将力直接从细胞外基质传递到细胞核。这些机械力导致 A 型核纤层蛋白的分子结构、修饰和组装状态发生变化。这反过来又激活了一种张力诱导的“内向外信号转导”，通过这种信号转导，细胞核反馈到细胞骨架和细胞外基质，以平衡外部和内部的力。这些功能调节分化，并且可能在核纤层蛋白相关疾病中受损，导致细胞表型，特别是在机械承重组织中。
