SMRT ‐mediated co‐shuttling enables export of class II a HDAC s independent of their CaM kinase phosphorylation sites

The Class II a histone deacetylases ( HDAC )4 and HDAC 5 play a role in neuronal survival and behavioral adaptation in the CNS . Phosphorylation at 2/3 N‐terminal sites promote their nuclear export. We investigated whether non‐canonical signaling routes to Class II a HDAC export exist because of their association with the co‐repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors ( SMRT ). We found that, while HDAC 5 and HDAC 4 mutants lacking their N‐terminal phosphorylation sites ( HDAC 4 MUT , HDAC 5 MUT ) are constitutively nuclear, co‐expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor ( BDNF ) signaling. We found that SMRT 's repression domain 3 ( RD 3) is critical for co‐shuttling of HDAC 5 MUT , consistent with the role for this domain in Class II a HDAC association. In the context of BDNF signaling, we found that HDAC 5 WT , which was more cytoplasmic than HDAC 5 MUT , accumulated in the nucleus after BDNF treatment. However, co‐expression of SMRT blocked BDNF ‐induced HDAC 5 WT import in a RD 3‐dependent manner. In effect, SMRT ‐mediated HDAC 5 WT export was opposing the BDNF ‐induced HDAC 5 nuclear accumulation observed in SMRT 's absence. Thus, SMRT 's presence may render Class II a HDAC s exportable by a wider range of signals than those which simply promote direct phosphorylation.