Abstract
The Class II histone deacetylase, HDAC6, has been shown to be involved in cell motility, aggresome formation and mitochondria transport. HDAC6 deacetylase activity regulates α-tubulin acetylation levels and thus plays a critical role in these processes. In turn, HDAC6 activity can be regulated by interaction with various proteins including multiple kinases. Kinase mediated phosphorylation of HDAC6 can lead to either increased or reduced activity. Our previous research has shown that sequestosome1/p62 (SQSTM1/p62) interacts with HDAC6 and regulates its activity. As SQSTM1/p62 is a scaffolding protein known to interact directly with the zeta isoform of Protein Kinase C (PKCζ), we sought to examine if HDAC6 could be a substrate for PKCζ phosphorylation and if so, how its activity might be regulated. Our data demonstrate that HDAC6 is not only present in a protein complex with PKCζ but can also be phosphorylated by PKCζ. We also show that specific phosphorylation of HDAC6 by PKCζ increases HDAC6 deacetylase activity resulting in reduced acetylated tubulin levels. Our findings provide novel insight into the molecular mechanism by which HDAC6, PKCζ and SQSTM1/p62 function together in protein aggregate clearance. These results also highlight a new research direction which may prove fruitful for understanding the underlying cause of several neurodegenerative diseases.
Highlights
The class II histone deacetylase 6 (HDAC6) has been found to be associated with diverse cellular processes
We show that specific phosphorylation of HDAC6 by PKCζ increases HDAC6 deacetylase activity resulting in reduced acetylated tubulin levels
We have previously shown that the activity of the histone deacetylase protein HDAC6 can be modulated by the scaffolding protein SQSTM1/p62 [20]
Summary
The class II histone deacetylase 6 (HDAC6) has been found to be associated with diverse cellular processes. Direct binding to tau, a microtubule associated stabilizing protein, directly inhibits HDAC6 deacetylase activity leading to impairment of autophagy [10]. The classical PKC isoform PKCα recruits and activates HDAC6 by phosphorylation This interaction modulates HDAC6’s deacetylation of β-catenin, enhancing its nuclear translocation and promoter binding [15, 16]. Two cytosolic aPKC isoforms have been shown to phosphorylate AurA, which targets HDAC6, stimulating tubulin deacetylation in primary cilia [19]. Our laboratory reported that the multimeric scaffolding protein SQSTM1/p62 binds to HDAC6, negatively regulating its deacetylase activity and affecting microtubule network equilibrium [20]. We reasoned that the SQSTM1/p62 binding partner PKCz could regulate HDAC6 deacetylase activity by direct phosphorylation of the HDAC6 protein. We show that HDAC6 is a substrate for PKCz phosphorylation and that the deacetylase activity of HDAC6 is induced by PKCz specific phosphorylation
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