UNC-45A breaks the microtubule lattice independently of its effects on non-muscle myosin II
UNC-45A breaks the microtubule lattice independently of its effects on non-muscle myosin II
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DOI：
10.1242/jcs.248815
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发表时间：
2021-01-01
影响因子：
4
通讯作者：
Bazzaro, Martina
中科院分区：
文献类型：
--
作者：
Habicht, Juri;Mooneyham, Ashley;Bazzaro, Martina
在无脊椎动物中，UNC-45调节肌球蛋白的稳定性和功能。脊椎动物有两种不同的蛋白亚型：UNC-45B，仅在肌肉细胞中表达；UNC-45A，在所有细胞中表达，参与调节非肌肉肌球蛋白II(NMII)和微管(MT)相关功能。在这里，我们证明，在体外以及在人和大鼠细胞中，UNC-45A与MT晶格结合，导致MT弯曲、断裂和解聚。此外，我们发现UNC-45A不依赖于其C端NMII结合结构域，甚至在NMII抑制剂blebbistatin存在的情况下也能破坏MTS的稳定。这些发现确认UNC-45A是一种新型的MT切断蛋白，在调节NMII活性和MT稳定性方面具有双重非互斥作用。由于许多人类疾病，从癌症到神经退行性疾病，都是由MT稳定性的放松引起的或与之相关的，我们的发现对MTS的生物学以及人类疾病的生物学和可能的治疗意义具有深远的影响。本文对该论文的联合第一作者进行了相关的第一人称采访。
In invertebrates, UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein: UNC-45B, expressed in muscle cells only, and UNC-45A, expressed in all cells and implicated in regulating both non-muscle myosin II (NMII)- and microtubule (MT)-associated functions. Here, we show that, in vitro and in human and rat cells, UNC-45A binds to the MT lattice, leading to MT bending, breakage and depolymerization. Furthermore, we show that UNC-45A destabilizes MTs independent of its C-terminal NMII-binding domain and even in the presence of the NMII inhibitor blebbistatin. These findings identified UNC-45A as a novel type of MT-severing protein with a dual non-mutually exclusive role in regulating NMII activity and MT stability. Because many human diseases, from cancer to neurodegenerative diseases, are caused by or associated with deregulation of MT stability, our findings have profound implications in the biology of MTs, as well as the biology of human diseases and possible therapeutic implications for their treatment.This article has an associated First Person interview with the joint first authors of the paper.