HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.
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.
Lee
Joo-Yong
JY
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Koga
Hiroshi
H
Kawaguchi
Yoshiharu
Y
Tang
Waixing
W
Wong
Esther
E
Gao
Ya-Sheng
YS
Pandey
Udai B
UB
Kaushik
Susmita
S
Tresse
Emily
E
Lu
Jianrong
J
Taylor
J Paul
JP
Cuervo
Ana Maria
AM
Yao
Tso-Pang
TP
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*
D000199:Actins; D029721:Drosophila Proteins; D025801:Ubiquitin; C425683:HDAC6 protein, Drosophila; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases