Cardiomyocyte mechanical memory is regulated through the talin interactome and DLC1 dependent regulation of RhoA
Cardiomyocyte mechanical memory is regulated through the talin interactome and DLC1 dependent regulation of RhoA
复制标题
心肌细胞机械记忆通过talin相互作用组和RhoA的DLC1依赖性调节进行调节
DOI：
10.1101/2023.07.19.549635
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Marhuenda E
中科院分区：
文献类型：
--
作者：
Marhuenda E
机械性能是健康或疾病中许多生物过程的线索。同样，在心脏中，越来越清楚的是，机械信号与疾病进展密切相关。心肌细胞通过整联蛋白和相关蛋白（包括作为组成部分的机械敏感蛋白talin）以costameres感知其环境的机械特性。我们以前的工作表明不同模式的talin张力，这取决于细胞外基质的刚度。在这里，我们想研究这如何导致下游机械转导的变化，进一步影响心肌细胞表型。结合免疫沉淀和荧光恢复后的光漂白（FRAP）实验，我们确定塔林相互作用蛋白DLC1，RIAM和桩蛋白每个优先结合塔林在特定的细胞外基质刚度和这种相互作用被保存，即使在没有张力。这证明了一种机械记忆，我们在小鼠心脏中进一步证实了这一点。机械记忆通过粘附相关激酶途径调节。使用LOVTRAP系统的光遗传学实验证实了单个蛋白质之间的直接竞争，这再次通过磷酸化改变。DLC1以刚度依赖性方式调节RhoA活性，DLC1的缺失和过表达均导致肌原纤维紊乱。该研究共同证明了将机械信息印记到塔林相互作用组中以微调RhoA活性的机制，对心脏健康和疾病产生影响。
Mechanical properties are cues for many biological processes in health or disease. Likewise, in the heart it is becoming clearer that mechanical signals are critically involved in the disease progression. Cardiomyocytes sense the mechanical properties of their environment at costameres through integrins and associated proteins, including the mechanosensitive protein talin as an integral component. Our previous work indicated different modes of talin tension, depending on the extracellular matrix stiffness. Here, we wanted to study how this leads to downstream mechanotransduction changes, further influencing the cardiomyocyte phenotype. Combining immunoprecipitations and Fluorescence Recovery after Photobleaching (FRAP) experiments, we identify that the talin interacting proteins DLC1, RIAM and paxillin each preferentially bind to talin at specific extracellular matrix stiffness and this interaction is preserved even in absence of tension. This demonstrates a mechanical memory, which we confirm furtherin vivoin mouse hearts. The mechanical memory is regulated through adhesion related kinase pathways. Optogenetic experiments using the LOVTRAP systems confirm direct competition between the individual proteins, which again is altered through phosphorylation. DLC1 regulates RhoA activity in a stiffness dependent way and both loss and overexpression of DLC1 results in myofibrillar disarray. Together the study demonstrates a mechanism of imprinting mechanical information into the talin-interactome to finetune RhoA activity, with impacts on cardiac health and disease.
登录
查看更多内容
RNA-Seq 鉴定了心力衰竭的新心肌基因表达特征。
影响因子：
4.4
作者：
Liu Y;Morley M;Brandimarto J;Hannenhalli S;Hu Y;Ashley EA;Tang WH;Moravec CS;Margulies KB;Cappola TP;Li M;MAGNet consortium
通讯作者：
MAGNet consortium
酪氨酸特异性去磷酸化-用碱性磷酸酶和表皮生长因子受体激酶进行磷酸化，如 31P NMR 波谱所证实。
影响因子：
2.7
作者：
K. Takahashi;M. Shimidzu;H. Shindo;T. Kawamoto;M. Nishi;U. Matsumoto;S. Taniguchi
通讯作者：
S. Taniguchi
通过表观遗传重塑存储的机械记忆降低了细胞的治疗潜力。
影响因子：
3.4
作者：
Scott,AdrienneK;Casas,Eduard;Schneider,StephanieE;Swearingen,AlisonR;VanDenElzen,CourtneyL;Seelbinder,Benjamin;Barthold,JeanneE;Kugel,JenniferF;Stern,JoshLewis;Foster,KylaJ;Emery,NancyC;Brumbaugh,Justin;Neu,CoreyP
通讯作者：
Neu,CoreyP
影响因子：
15.9
作者：
Sah, VP;Minamisawa, S;Brown, JH
通讯作者：
Brown, JH
DOI：
10.1016/j.jbc.2021.100837
发表时间：
2021-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Gough RE;Jones MC;Zacharchenko T;Le S;Yu M;Jacquemet G;Muench SP;Yan J;Humphries JD;Jørgensen C;Humphries MJ;Goult BT
通讯作者：
Goult BT