title: HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.
abstract: Autophagy is primarily considered a non-selective degradation process induced by starvation. Nutrient-independent basal autophagy, in contrast, imposes intracellular QC by selective disposal of aberrant protein aggregates and damaged organelles, a process critical for suppressing neurodegenerative diseases. The molecular mechanism that distinguishes these two fundamental autophagic responses, however, remains mysterious. Here, we identify the ubiquitin-binding deacetylase, histone deacetylase-6 (HDAC6), as a central component of basal autophagy that targets protein aggregates and damaged mitochondria. Surprisingly, HDAC6 is not required for autophagy activation; rather, it controls the fusion of autophagosomes to lysosomes. HDAC6 promotes autophagy by recruiting a cortactin-dependent, actin-remodelling machinery, which in turn assembles an F-actin network that stimulates autophagosome-lysosome fusion and substrate degradation. Indeed, HDAC6 deficiency leads to autophagosome maturation failure, protein aggregate build-up, and neurodegeneration. Remarkably, HDAC6 and F-actin assembly are completely dispensable for starvation-induced autophagy, uncovering the fundamental difference of these autophagic modes. Our study identifies HDAC6 and the actin cytoskeleton as critical components that define QC autophagy and uncovers a novel regulation of autophagy at the level of autophagosome-lysosome fusion.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Waixing
authors.initials: W
authors.lastname: Tang
authors.forename: Esther
authors.initials: E
authors.lastname: Wong
authors.forename: Ya-Sheng
authors.initials: YS
authors.lastname: Gao
authors.forename: Udai B
authors.initials: UB
authors.lastname: Pandey
authors.forename: Susmita
authors.initials: S
authors.lastname: Kaushik
authors.forename: Emily
authors.initials: E
authors.lastname: Tresse
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000199:Actins; D029721:Drosophila Proteins; D025801:Ubiquitin; C425683:HDAC6 protein, Drosophila; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases