Histone deacetylase 6 interacts with the microtubule-associated protein tau.
Histone deacetylase 6 (HDAC6), a unique cytoplasmic deacetylase, likely plays a role in neurodegeneration by coordinating cell responses to abnormal protein aggregation. Here, we provide in vitro and in vivo evidence that HDAC6 interacts with tau, a microtubule-associated protein that forms neurofibrillary tangles in Alzheimer's disease. This interaction is mediated by the microtubule-binding domain on tau and the Ser/Glu tetradecapeptide domain on HDAC6. Treatment with tubacin, a selective inhibitor of tubulin deacetylation activity of HDAC6, did not disrupt HDAC6-tau interaction. Nonetheless tubacin treatment attenuated site-specific tau phosphorylation, as did shRNA-mediated knockdown of HDAC6. Proteasome inhibition potentiated HDAC6-tau interactions and facilitated the concentration and co-localization of HDAC6 and tau in a perinuclear aggresome-like compartment, independent of HDAC6 tubulin deacetylase activity. Furthermore, we observed that in Alzheimer's disease brains the protein level of HDAC6 was significantly increased. These findings establish HDAC6 as a tau-interacting protein and as a potential modulator of tau phosphorylation and accumulation.
Ding
Huiping
H
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Dolan
Philip J
PJ
Johnson
Gail V W
GV
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002451:Cell Compartmentation / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015388:Organelles / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
D000813:Anilides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D016875:tau Proteins; C474316:tubacin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases