Abstract
Cell migration plays pivotal roles in many biological processes; however, its underlying mechanism remains unclear. Here, we find that NudC-like protein 2 (NudCL2), a cochaperone of heat shock protein 90 (Hsp90), modulates cell migration by stabilizing both myosin-9 and lissencephaly protein 1 (LIS1). Either knockdown or knockout of NudCL2 significantly increases single-cell migration, but has no significant effect on collective cell migration. Immunoprecipitation–mass spectrometry and western blotting analyses reveal that NudCL2 binds to myosin-9 in mammalian cells. Depletion of NudCL2 not only decreases myosin-9 protein levels, but also results in actin disorganization. Ectopic expression of myosin-9 efficiently reverses defects in actin disorganization and single-cell migration in cells depleted of NudCL2. Interestingly, knockdown of myosin-9 increases both single and collective cell migration. Depletion of LIS1, a NudCL2 client protein, suppresses both single and collective cell migration, which exhibits the opposite effect compared with myosin-9 depletion. Co-depletion of myosin-9 and LIS1 promotes single-cell migration, resembling the phenotype caused by NudCL2 depletion. Furthermore, inhibition of Hsp90 ATPase activity also reduces the Hsp90-interacting protein myosin-9 stability and increases single-cell migration. Forced expression of Hsp90 efficiently reverses myosin-9 protein instability and the defects induced by NudCL2 depletion, but not vice versa. Taken together, these data suggest that NudCL2 plays an important role in the precise regulation of cell migration by stabilizing both myosin-9 and LIS1 via Hsp90 pathway.
Highlights
Cell migration plays a pivotal role in many fundamental biological processes, including embryonic development, tissue homeostasis, immune surveillance, and wound healing[1,2,3]
Our results strongly indicate that NudC-like protein 2 (NudCL2) is essential for single-cell migration in mammalian cells
We find that either knockdown of NudCL2 or knockout of NudCL2 significantly increased single-cell migration, but not collective cell migration in mammalian cells (Fig. 1, Supplementary Figs. 1–3)
Summary
Cell migration plays a pivotal role in many fundamental biological processes, including embryonic development, tissue homeostasis, immune surveillance, and wound healing[1,2,3]. There exist two basic types of cell migration in vivo and in vitro: single-cell migration (the movement of cells independent of each other) and collective cell migration Accumulating studies indicate that the dynamics of actin cytoskeleton regulates cell migration spatially and temporally[7]. Myosins are a large family of actin-based molecular motors that bind actin filaments to generate force and movement[8,9]. NM IIA is found to polymerize into bipolar minifilaments that interact with actin filaments via their ATPase head. NM IIA minifilaments slide actin filaments in an anti-parallel
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