A kinesin-1 variant reveals motor-induced microtubule damage in cells.
A kinesin-1 variant reveals motor-induced microtubule damage in cells.
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驱动蛋白-1变体揭示了细胞中运动诱导的微管损伤。
DOI：
10.1016/j.cub.2022.04.020
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发表时间：
2022-06-06
期刊：
影响因子：
9.2
通讯作者：
Verhey, Kristen J.
中科院分区：
文献类型：
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作者：
Budaitis, Breane G.;Badieyan, Somayesadat;Yue, Yang;Blasius, T. Lynne;Reinemann, Dana N.;Lang, Matthew J.;Cianfrocco, Michael A.;Verhey, Kristen J.
驱动蛋白驱动细胞货物的运输，因为它们沿着沿着微管轨道行走;然而，最近的工作表明，驱动蛋白沿着沿着微管行走的物理行为可以对微管晶格施加应力。在这里，我们描述了一个驱动蛋白-1 KIF 5C突变体与野生型电机相比，在微管晶格中产生损伤位点的能力增加。在培养的细胞中突变马达的表达导致微管断裂和碎片化，这表明具有增加的损伤活性的驱动蛋白-1变体在进化过程中会被选择。损伤微管的能力增加不是由于突变马达的运动特性增强，因为具有类似单马达运动特性的驱动蛋白-3马达KIF 1A的表达也引起微管暂停、弯曲和屈曲增加，但不断裂。在细胞中，运动诱导的微管断裂不能通过增加α-微管蛋白K40乙酰化（一种已知增加微管灵活性的翻译后修饰）来预防。在体外，由野生型KIF 5C诱导的晶格损伤由可溶性微管蛋白修复，并导致增加的救援和整体微管生长，而由KIF 5C突变体诱导的晶格损伤导致更大的修复位点，使得微管在机械应力下容易断裂和碎裂。这些结果表明，驱动蛋白-1运动性导致细胞中微管晶格的缺陷和损伤。虽然细胞具有修复晶格损伤的能力，但超过这种能力的条件会导致微管断裂和碎片化，并可能导致人类疾病。Budaitis等人证明，驱动蛋白-1在沿着微管蛋白亚基步进时损害微管。运动引起的损伤使微管对机械应力敏感。虽然运动诱导的损伤可以修复，但过度的运动诱导的损伤会导致细胞中的微管断裂和碎片化，并可能导致疾病。
Kinesins drive the transport of cellular cargoes as they walk along microtubule tracks; however, recent work has suggested that the physical act of kinesins walking along microtubules can stress the microtubule lattice. Here, we describe a kinesin-1 KIF5C mutant with an increased ability to generate damage sites in the microtubule lattice as compared with the wild-type motor. The expression of the mutant motor in cultured cells resulted in microtubule breakage and fragmentation, suggesting that kinesin-1 variants with increased damage activity would have been selected against during evolution. The increased ability to damage microtubules is not due to the enhanced motility properties of the mutant motor, as the expression of the kinesin-3 motor KIF1A, which has similar single-motor motility properties, also caused increased microtubule pausing, bending, and buckling but not breakage. In cells, motor-induced microtubule breakage could not be prevented by increased α-tubulin K40 acetylation, a post-translational modification known to increase microtubule flexibility. In vitro, lattice damage induced by wild-type KIF5C was repaired by soluble tubulin and resulted in increased rescues and overall microtubule growth, whereas lattice damage induced by the KIF5C mutant resulted in larger repair sites that made the microtubule vulnerable to breakage and fragmentation when under mechanical stress. These results demonstrate that kinesin-1 motility causes defects in and damage to the microtubule lattice in cells. While cells have the capacity to repair lattice damage, conditions that exceed this capacity result in microtubule breakage and fragmentation and may contribute to human disease. Budaitis et al. demonstrate that kinesin-1 damages the microtubule while stepping along tubulin subunits. Motor-induced damage makes microtubules sensitive to mechanical stress. Although motor-induced damage can be repaired, excessive motor-induced damage results in microtubule breakage and fragmentation in cells and may contribute to disease.
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