aPKC phosphorylation of HDAC6 results in increased deacetylation activity

• Published in: PloS one 2015-04, Vol.10 (4), p.e0123191
• Main Authors: Du, Yifeng, Seibenhener, Michael L, Yan, Jin, Jiang, Jianxiong, Wooten, Michael C
• Format: Article
• Language: English
• Subjects: Acetylation; Alzheimer's disease; Animals; Autophagy (Cytology); Cell adhesion & migration; Cell Line; Deacetylation; Genetic aspects; Histone deacetylase; Histone Deacetylase 6; Histone Deacetylases - metabolism; Humans; Immunoglobulins; Isoenzymes; Kinases; Mice; Mitochondria; Motility; Neurodegenerative diseases; Neurological diseases; Phosphorylation; Phosphotransferases; Physiological aspects; Protein kinase C; Protein Kinase C - metabolism; Proteins; Scaffolding; Substrates; Tubulin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0123191

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.