Histone deacetylase 4 possesses intrinsic nuclear import and export signals

Nucleocytoplasmic trafficking of histone deacetylase 4 (HDAC4) plays an imp ortant role in regulating its function, and binding of 14-3-3 proteins is n ecessary for its cytoplasmic retention. Here, we report the identification of nuclear import and export sequences of HDAC4. While its N-terminal 118 r esidues modulate the nuclear localization, residues 244 to 279 constitute a n authentic, strong nuclear localization signal. Mutational analysis of thi s signal revealed that three arginine-lysine clusters are necessary for its nuclear import activity. As for nuclear export, leucine-rich sequences loc ated in the middle part of HDAC4 do not function as nuclear export signals. By contrast, a hydrophobic motif (MXXLXVXV) located at the C-terminal end serves as a nuclear export signal that is necessary for cytoplasmic retenti on of HDAC4. This motif is required for CRM1-mediated nuclear export of HDA C4. Furthermore, binding of 14-3-3 proteins promotes cytoplasmic localizati on of HDAC4 by both inhibiting its nuclear import and stimulating its nucle ar export. Unlike wild-type HDAC4, a point mutant with abrogated MEF2-bindi ng ability remains cytoplasmic upon exogenous expression of MEF2C, supporti ng the notion that direct MEF2 binding targets HDAC4 to the nucleus. Theref ore, HDAC4 possesses intrinsic nuclear import and export signals for its dy namic nucleocytoplasmic shuttling, and association with 14-3-3 and MEF2 pro teins affects such shuttling and thus directs HDAC4 to the cytoplasm and th e nucleus, respectively.