Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart
Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart
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DOI：
10.1161/circresaha.111.245787
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发表时间：
2011-09-16
影响因子：
20.1
通讯作者：
Chien, Kenneth R.
中科院分区：
文献类型：
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作者：
Knoell, Ralph;Linke, Wolfgang A.;Chien, Kenneth R.
基本原理：Telethonin（也称为肌联蛋白帽或t-cap）是一种具有独特β折叠结构的19 kDa Z盘蛋白，假设以回文方式与肌联蛋白的N-末端部分组装，并构成参与心脏机械感知过程的信号体。此外，各种telethonin突变与几种不同疾病的发展有关;然而，对telethonin的潜在分子机制和体内功能知之甚少。目的：在这里，我们旨在研究telethonin在体内的作用，并确定其突变导致疾病的分子机制。方法和结果：通过使用各种不同的基因改变的动物模型和生物物理实验，我们表明，与以前的观点相反，telethonin是不是一个必不可少的组成部分的肌联蛋白锚定系统，也不是删除的基因或心脏特异性过表达与自发性心脏表型。相反，额外的肌联蛋白锚定位点，如肌动蛋白-肌联蛋白通过α-辅肌动蛋白交联，足以维持Z-盘稳定性，尽管telethonin的损失。我们证明，一个主要的新功能telethonin是调节营业额的促凋亡肿瘤抑制基因p53后，在核室的生物力学应力，从而连接telethonin，一种蛋白质，众所周知是目前在Z-磁盘，直接凋亡（“mechanoptosis”）。此外，Telethonin mRNA的丢失和这种蛋白质的核积累与人类心力衰竭有关，这种作用可能有助于这些心脏中发现的细胞凋亡率的提高。Telethonin基因敲除小鼠在基础条件下不会表现出心脏发育或心脏功能缺陷，但在生物力学应激后会出现心力衰竭，这至少部分是由于心肌细胞的凋亡，这种效应也可能在人类心力衰竭中发挥作用。(Circ Res. 2011; 109：758-769）。
Rationale: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique beta-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.Objective: Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation.Methods and Results: By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via alpha-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.Conclusions: Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure. (Circ Res. 2011; 109: 758-769.)