HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.
CNS neurons are endowed with the ability to recover from cytotoxic insults associated with the accumulation of proteinaceous polyglutamine aggregates via a process that appears to involve capture and degradation of aggregates by autophagy. The ubiquitin-proteasome system protects cells against proteotoxicity by degrading soluble monomeric misfolded aggregation-prone proteins but is ineffective against, and impaired by, non-native protein oligomers. Here we show that autophagy is induced in response to impaired ubiquitin proteasome system activity. We show that ATG proteins, molecular determinants of autophagic vacuole formation, and lysosomes are recruited to pericentriolar cytoplasmic inclusion bodies by a process requiring an intact microtubule cytoskeleton and the cytoplasmic deacetylase HDAC6. These data suggest that HDAC6-dependent retrograde transport on microtubules is used by cells to increase the efficiency and selectivity of autophagic degradation.
Iwata
Atsushi
A
Department of Biological Sciences, BIO-X Program, Stanford University, Stanford, California 94305-5430, USA.
Riley
Brigit E
BE
Johnston
Jennifer A
JA
Kopito
Ron R
RR
D001343:Autophagy; D001692:Biological Transport; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D008247:Lysosomes / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry; D014617:Vacuoles / Q000378:metabolism
D018076:DNA, Complementary; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases