Desmin intermediate filaments and tubulin detyrosination stabilize growing microtubules in the cardiomyocyte.
Desmin intermediate filaments and tubulin detyrosination stabilize growing microtubules in the cardiomyocyte.
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DOI：
10.1007/s00395-022-00962-3
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发表时间：
2022-11-03
影响因子：
9.5
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在心力衰竭中，大量的去酪氨酸后微管增加使心肌细胞变硬并阻碍其收缩功能。脱酪氨酸促进微管、结蛋白中间丝和肌节之间的相互作用，以增加细胞骨架刚度，但其发生机制尚不清楚。我们推测，脱酪氨酸可能调节动态微管的生长和收缩，以促进与结蛋白和肌节的相互作用。通过结合生物化学测定和直接观察成年心肌细胞中的微管加端，我们发现，结蛋白是需要稳定在肌节Z-盘的水平，其中结蛋白也拯救收缩微管从继续解聚的微管增长。此外，将脱酪氨酸作用（即酪氨酸作用）降低到低于基础水平促进了微管的频繁解聚和较低效率的生长。这是伴随着酪氨酸促进微管与末端结合蛋白1（EB 1）和含CAP-Gly结构域的连接蛋白1（CLIP 1/CLIP 170）的解聚蛋白复合物的相互作用。酪氨酸化微管的动态生长和收缩减少了它们在Z盘区域稳定相互作用的机会，与酪氨酸化整体降低微管稳定性一致。这些数据为中间丝和微管蛋白去酪氨酸化如何建立长寿命和物理增强的微管提供了模型，这些微管包裹心肌细胞，并为旨在恢复酪氨酸化以治疗心脏病的策略提供了作用机制和治疗指数。 在线版本包含补充材料，可通过10.1007/s 00395 -022-00962-3获得。
In heart failure, an increased abundance of post-translationally detyrosinated microtubules stiffens the cardiomyocyte and impedes its contractile function. Detyrosination promotes interactions between microtubules, desmin intermediate filaments, and the sarcomere to increase cytoskeletal stiffness, yet the mechanism by which this occurs is unknown. We hypothesized that detyrosination may regulate the growth and shrinkage of dynamic microtubules to facilitate interactions with desmin and the sarcomere. Through a combination of biochemical assays and direct observation of growing microtubule plus-ends in adult cardiomyocytes, we find that desmin is required to stabilize growing microtubules at the level of the sarcomere Z-disk, where desmin also rescues shrinking microtubules from continued depolymerization. Further, reducing detyrosination (i.e. tyrosination) below basal levels promotes frequent depolymerization and less efficient growth of microtubules. This is concomitant with tyrosination promoting the interaction of microtubules with the depolymerizing protein complex of end-binding protein 1 (EB1) and CAP-Gly domain-containing linker protein 1 (CLIP1/CLIP170). The dynamic growth and shrinkage of tyrosinated microtubules reduce their opportunity for stabilizing interactions at the Z-disk region, coincident with tyrosination globally reducing microtubule stability. These data provide a model for how intermediate filaments and tubulin detyrosination establish long-lived and physically reinforced microtubules that stiffen the cardiomyocyte and inform both the mechanism of action and therapeutic index for strategies aimed at restoring tyrosination for the treatment of cardiac disease. The online version contains supplementary material available at 10.1007/s00395-022-00962-3.