Nuclear export of actin: a novel mechanism regulating the subcellular localization of a major cytoskeletal protein

Actin is a highly conserved, ubiquitous cytoskeletal protein, which is essential for multiple cellular functions, Despite its small size (M-r = 42 000), unpolymerized forms of actin, as well as polymerized forms, exist primarily in the cytoplasm, excluded from the nucleus, Although spatial control of actin is crucially important, the molecular mechanisms ensuring the cytoplasmic localization of unpolymerized actin have not been revealed so far, In this paper we report that actin contains two leucine-rich type nuclear export signal (NES) sequences in the middle part of the molecule, which are both shown to be functional, Monomeric actin, when injected into the nucleus, was rapidly exported in a manner which was sensitive to leptomycin B (LMB), a specific inhibitor of NES-dependent nuclear export, LMB treatment of cells prevented nuclear exclusion of endogenous actin, inducing its nuclear accumulation, Furthermore, actin mutants with disrupted NESs accumulated in the nucleus, Expression of these NES-disrupted actin mutants, but not of wildtype actin, induced a decrease in the proliferative potential of the cell, These results reveal a novel molecular mechanism controlling the subcellular distribution of actin.