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.
Bibliographical noteFunding Information:
This work was supported by the US Department of Defense Ovarian Cancer Research Program (OC160377), the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund and the National Institute of General Medical Sciences (R01-GM130800 to M.B.; R35-GM126974 to M.K.G.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Deposited in PMC for release after 12 months.
- Microtubule lattice
- Microtubule-destabilizing proteins