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

Publication ,  Journal Article
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 in: EMBO J
March 3, 2010

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.

Duke Scholars

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Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

March 3, 2010

Volume

29

Issue

5

Start / End Page

969 / 980

Location

England

Related Subject Headings

  • Ubiquitin
  • Phagosomes
  • Microscopy, Fluorescence
  • Mice
  • Lysosomes
  • Immunohistochemistry
  • Histone Deacetylases
  • Histone Deacetylase 6
  • Drosophila Proteins
  • Drosophila
 

Citation

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Lee, J.-Y., Koga, H., Kawaguchi, Y., Tang, W., Wong, E., Gao, Y.-S., … Yao, T.-P. (2010). HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J, 29(5), 969–980. https://doi.org/10.1038/emboj.2009.405
Lee, Joo-Yong, Hiroshi Koga, Yoshiharu Kawaguchi, Waixing Tang, Esther Wong, Ya-Sheng Gao, Udai B. Pandey, et al. “HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.EMBO J 29, no. 5 (March 3, 2010): 969–80. https://doi.org/10.1038/emboj.2009.405.
Lee J-Y, Koga H, Kawaguchi Y, Tang W, Wong E, Gao Y-S, et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 2010 Mar 3;29(5):969–80.
Lee, Joo-Yong, et al. “HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.EMBO J, vol. 29, no. 5, Mar. 2010, pp. 969–80. Pubmed, doi:10.1038/emboj.2009.405.
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. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 2010 Mar 3;29(5):969–980.

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

March 3, 2010

Volume

29

Issue

5

Start / End Page

969 / 980

Location

England

Related Subject Headings

  • Ubiquitin
  • Phagosomes
  • Microscopy, Fluorescence
  • Mice
  • Lysosomes
  • Immunohistochemistry
  • Histone Deacetylases
  • Histone Deacetylase 6
  • Drosophila Proteins
  • Drosophila