HDAC6 and Microtubules Are Required for Autophagic Degradation of Aggregated Huntingtin*

By A. Iwata, B. Riley, J. A. Johnston, R. Kopito. Journal of Biological Chemistry, 2005

749 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/567043ff452c2b79b1f364775f2ce21764586866

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Citations in the corpus

Eaten alive: a history of macroautophagy (2010, background): “Furthermore, autophagy may eliminate protein aggregates through a selective mechanis”
Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. (2007, methodology): “We retested 72 total primary assay positives, from which we identified a structurally nonredundant set of 21 SMIRs (4-24) and 12 SMERs (25-36) (Supplementary Fig.”
Autophagy Inhibition Compromises Degradation of Ubiquitin-Proteasome Pathway Substrates (2009, positive): “The inhibition of UPS flux by autophagy compromise is unexpected, as autophagy upregulation has been reported as a compensatory response after proteasome inhibition ( Iwata et al., 2005; Pandey et al., 2007).”
Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. (2011, background): “, 2009), as autophagy can remove protein aggregates (Bjørkøy et al., 2005; Filimonenko et al., 2010; Iwata et al., 2005; Martinez-Vicente et al., 2010; Ravikumar et al., 2004; Yamamoto et al., 2006).”
Multiple roles of HDAC inhibition in neurodegenerative conditions (2009, background): “It is well known that the genetic mutation responsible for HD is an expansion of a CAG trinucleotide repeat encoding polyglutamine (polyQ) in the first exon of the huntingtin (HTT) gene.”
Molecular mechanisms and potential therapeutical targets in Huntington's disease. (2010, background): “The use of tubacin, a selective HDAC6 inhibitor, leads to a rescue of the mutant huntingtin aggregation (277).”
FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. (2007, result): “It has been reported that inhibition of proteasomes leads to a compensatory increase in autophagy (Iwata et al., 2005), but no such change was observed in our studies.”
Cellular strategies for controlling protein aggregation (2010, background): “Initially, aggregates of proteins involved in neurodegenerative disease, such as α-synuclein or mutant huntingtin, were identified as substrates for this type of autophag”
Molecular chaperones in protein folding and proteostasis (2011, background): “Interestingly, whereas the clearance of misfolded protein species by the UPS requires that these molecules are maintained in a non-aggregated state by chaperones, disposal by autophagy is thought to involve active mechanisms to force such molecules into larger, presumably less toxic, aggregate”