FHODs: Nuclear tethered formins for nuclear mechanotransduction.
FHODs: Nuclear tethered formins for nuclear mechanotransduction.
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DOI：
10.3389/fcell.2023.1160219
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发表时间：
2023
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
在这篇综述中，我们讨论了FHOD formins，重点是最近的研究，揭示了一个新的作用，他们作为关键环节的核机械转导。脊椎动物中的FHOD家族包括两种结构相关的蛋白质，FHOD 1和FHOD 3。它们相似的生化特性表明它们的功能是重叠和冗余的。FHOD 1广泛表达，FHOD 3表达较少，在表达特定剪接异构体的骨骼肌（FHOD 1）和心肌（FHOD 3）中表达最高。与其他形式蛋白不同，FHOD具有较强的F-肌动蛋白成束活性和相对较弱的肌动蛋白聚合活性。这些活动由ROCK和Src激酶磷酸化调节;成束还由ERK 1/2激酶调节。FHOD在formin中是独特的，它们通过直接、高亲和力结合外核膜蛋白nesprin-1G和nesprin-2G与核膜结合。最近的晶体结构揭示了一个保守的主题之间的相互作用的血影蛋白重复序列（SR）的nesprin-1G/2G和一个网站相邻的调控结构域的氨基末端的FHODs。Nesprins是LINC（核骨架和细胞骨架的连接体）复合物的组分，其跨越核膜并介导核和细胞骨架之间的机械力的双向传递。FHODs相互作用附近的肌动蛋白结合的钙调蛋白同源（CH）结构域的nesprin-1G/2G，使分支连接到肌动蛋白丝，推测加强相互作用。在细胞水平上，FHOD与外核膜的拴系将核周肌动蛋白阵列机械地偶联到细胞核，以将其移动并定位在成纤维细胞、心肌细胞和潜在的其他细胞中。FHODs还在细胞迁移过程中的粘附成熟和肌节的产生中发挥作用，这些活动远离细胞核，但仍然受到它的影响。人类遗传学研究已经确定了与扩张和肥大性心肌病相关的多种FHOD 3变体，其中许多突变映射到FHOD 3结构域中的“热点”。我们讨论如何FHOD 1/3的作用，加强LINC复合物和连接到核周肌动蛋白有助于机械活性组织，如横纹肌的功能。
In this review, we discuss FHOD formins with a focus on recent studies that reveal a new role for them as critical links for nuclear mechanotransduction. The FHOD family in vertebrates comprises two structurally related proteins, FHOD1 and FHOD3. Their similar biochemical properties suggest overlapping and redundant functions. FHOD1 is widely expressed, FHOD3 less so, with highest expression in skeletal (FHOD1) and cardiac (FHOD3) muscle where specific splice isoforms are expressed. Unlike other formins, FHODs have strong F-actin bundling activity and relatively weak actin polymerization activity. These activities are regulated by phosphorylation by ROCK and Src kinases; bundling is additionally regulated by ERK1/2 kinases. FHODs are unique among formins in their association with the nuclear envelope through direct, high affinity binding to the outer nuclear membrane proteins nesprin-1G and nesprin-2G. Recent crystallographic structures reveal an interaction between a conserved motif in one of the spectrin repeats (SRs) of nesprin-1G/2G and a site adjacent to the regulatory domain in the amino terminus of FHODs. Nesprins are components of the LINC (linker of nucleoskeleton and cytoskeleton) complex that spans both nuclear membranes and mediates bidirectional transmission of mechanical forces between the nucleus and the cytoskeleton. FHODs interact near the actin-binding calponin homology (CH) domains of nesprin-1G/2G enabling a branched connection to actin filaments that presumably strengthens the interaction. At the cellular level, the tethering of FHODs to the outer nuclear membrane mechanically couples perinuclear actin arrays to the nucleus to move and position it in fibroblasts, cardiomyocytes, and potentially other cells. FHODs also function in adhesion maturation during cell migration and in the generation of sarcomeres, activities distant from the nucleus but that are still influenced by it. Human genetic studies have identified multiple FHOD3 variants linked to dilated and hypertrophic cardiomyopathies, with many mutations mapping to “hot spots” in FHOD3 domains. We discuss how FHOD1/3’s role in reinforcing the LINC complex and connecting to perinuclear actin contributes to functions of mechanically active tissues such as striated muscle.
DOI：
10.1002/cm.21639
发表时间：
2020-10
期刊：
Cytoskeleton (Hoboken, N.J.)
影响因子：
--
作者：
Sundaramurthy S;Votra S;Laszlo A;Davies T;Pruyne D
通讯作者：
Pruyne D