The vertebrate isoform of UNC45, UNC-45A, has been mostly studied in the context of non-muscle myosin II (NMII) regulation, where its binding is required for NMII folding, actin binding and stress fibre assembly. Martina Bazzaro and her colleagues have previously shown that, in addition to having a role in NMIIA regulation, UNC-45A is involved in destabilizing microtubules (MTs). In their article, Martina Bazzaro and colleagues (Habicht et al., 2020) investigated how UNC-45A achieves depolymerisation of MTs. To this end, the authors have followed live the binding of UNC-45A–GFP to MTs and the behaviour of MTs in the presence of UNC-45A. UNC-45A bound robustly along the length of MTs in vitro, and its presence shortened MTs and caused them to appear kinked and have gaps. The role of UNC-45A in MT destabilization is not dependent on NMII, and the authors, using N- or C-terminal deletion of the protein in vitro and in cells, were able to dissect the distinct roles of the protein and attribute them to distinct protein domains. Furthermore, overexpression of UNC-45A in rat lung fibroblast cells increased the breakages in MTs, even in the C-terminal-deleted (myosin II-binding domain) mutant, confirming the MT-destabilizing properties of the protein and the independence from its NMII regulatory role. This dual non-mutually exclusive role of UNC-45A in regulating actomyosin and MT stability may have implications in diseases associated with deregulation of MT stability, like cancers and neurodegenerative conditions.
