UNC-45A Weakens and Breaks MT Lattice Independent of its Effect on Non-Muscle Myosin II

Abstract

In invertebrates, the member of UCS domain family UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein: UNC-45B, expressed in muscle cells only and responsible for muscle myosin folding and assembly, 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 for the first time that in vitro UNC-45A binds to the lattice of paclitaxel-stabilized MTs, and destabilizes the lattice integrity, leading to MT depolymerization in a dose-dependent manner. We also show that UNC-45A overexpression causes a dramatic loss of MT mass and increase in MT breakages in cells lacking the MT stabilizing protein tau. We also show for the first time that, both in vitro and in cells, that UNC-45A destabilizes MTs independent of its NMII C-terminal binding domain and destabilization occurs even in presence of the NMII inhibitor blebbistatin. These findings are consistent with a not mutually exclusive but rather dual role of UNC-45A in regulating NMII activity and MT stability. As many human diseases, from cancer to neurodegenerative diseases are caused by or associated with deregulation of MT stability, our findings are important as to ongoing and future studies aimed to understand the mechanisms through which UNC-45A regulates MT stability in the context of health and disease. This includes providing a novel platform for therapeutic intervention of cancer and neurodegenerative diseases.