HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Lee, J-Y; Koga, H; Kawaguchi, Y; Tang, W; Wong, E; Gao, Y-S; Pandey, UB; Kaushik, S; Tresse, E; Lu, J; Taylor, JP; Cuervo, AM; Yao, T-P
Published Date
- March 3, 2010
Published In
Volume / Issue
- 29 / 5
Start / End Page
- 969 - 980
PubMed ID
- 20075865
Pubmed Central ID
- 20075865
Electronic International Standard Serial Number (EISSN)
- 1460-2075
Digital Object Identifier (DOI)
- 10.1038/emboj.2009.405
Language
- eng
Conference Location
- England