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

Joo Yong Lee, Hiroshi Koga, Yoshiharu Kawaguchi, Waixing Tang, Esther Wong, Ya Sheng Gao, Udai B. Pandey, Susmita Kaushik, Emily Tresse, Jianrong Lu, J. Paul Taylor, Ana Maria Cuervo, Tso Pang Yao

Research output: Contribution to journalArticle

484 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)969-980
Number of pages12
JournalEMBO Journal
Volume29
Issue number5
DOIs
StatePublished - Mar 1 2010

Keywords

  • Actin
  • Autophagosome-lysosome fusion
  • Autophagy
  • HDAC6
  • Neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Lee, J. Y., Koga, H., Kawaguchi, Y., Tang, W., Wong, E., Gao, Y. S., Pandey, U. B., Kaushik, S., Tresse, E., Lu, J., Taylor, J. P., Cuervo, A. M., & Yao, T. P. (2010). HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO Journal, 29(5), 969-980. https://doi.org/10.1038/emboj.2009.405