title: aPKC phosphorylation of HDAC6 results in increased deacetylation activity.
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.
authors: Department of Biological Sciences, Cellular and Molecular Biosciences Program, Auburn University, AL, 36849, United States of America.
authors: Yifeng
authors: Y
authors: Du
authors: Department of Biological Sciences, Cellular and Molecular Biosciences Program, Auburn University, AL, 36849, United States of America.
authors: Michael L
authors: ML
authors: Seibenhener
authors: Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, United States of America.
authors: Jin
authors: J
authors: Yan
authors: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, United States of America.
authors: Jianxiong
authors: J
authors: Jiang
authors: Department of Biological Sciences, Cellular and Molecular Biosciences Program, Auburn University, AL, 36849, United States of America.
authors: Michael C
authors: MC
authors: Wooten
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes; D051379:Mice; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; C115015:PKC-3 protein; D011493:Protein Kinase C; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases