Molecular Mechanism Of NudCL2 In Cell Movement Regulation

Cell migration plays pivotal roles in many biological processes,such as embryonic development,tissue repair,and immune response.Its abnormalities are involved in a variety of human diseases,such as autoimmune syndrome,mental retardation,and cancer.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.Western blot analyses reveal that depletion of NudCL2 not only decreases myosin-9 protein levels,but also results in actin disorganization.Ectopic expression of myosin-9efficiently 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 withmyosin-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 myosin-9 stability and increases single-cell migration.Forced expression of Hsp90 efficiently reverses myosin-9 and LIS1 proteins instability,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.Our research reveals new functions of NudCL2 in cell migration,providing potential new therapy target for cell migration related diseases.