4.5 Article

UNC-45A breaks the microtubule lattice independently of its effects on non-muscle myosin II

期刊

JOURNAL OF CELL SCIENCE
卷 134, 期 1, 页码 -

出版社

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.248815

关键词

UNC-45A; Microtubules; Microtubule lattice; Microtubule-destabilizing proteins; Tau

资金

  1. US Department of Defense Ovarian Cancer Research Program [OC160377]
  2. Minnesota Ovarian Cancer Alliance
  3. Randy Shaver Cancer Research and Community Fund
  4. National Institute of General Medical Sciences [R01-GM130800, R35-GM126974]
  5. CDMRP [OC160377, 917602] Funding Source: Federal RePORTER

向作者/读者索取更多资源

UNC-45A is identified as a novel type of microtubule-severing protein, which can disrupt microtubule stability and also be involved in regulating the activity of non-muscle myosin II. This finding has significant implications in the biology of microtubules and human diseases.
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.

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