HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.

Published

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 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

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/emboj.2009.405

Language

  • eng