Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton.
Autophagy has been predominantly studied as a nonselective self-digestion process that recycles macromolecules and produces energy in response to starvation. However, autophagy independent of nutrient status has long been known to exist. Recent evidence suggests that this form of autophagy enforces intracellular quality control by selectively disposing of aberrant protein aggregates and damaged organelles--common denominators in various forms of neurodegenerative diseases. By definition, this form of autophagy, termed quality-control (QC) autophagy, must be different from nutrient-regulated autophagy in substrate selectivity, regulation and function. We have recently identified the ubiquitin-binding deacetylase, HDAC6, as a key component that establishes QC. HDAC6 is not required for autophagy activation per se; rather, it is recruited to ubiquitinated autophagic substrates where it stimulates autophagosome-lysosome fusion by promoting F-actin remodeling in a cortactin-dependent manner. Remarkably, HDAC6 and cortactin are dispensable for starvation-induced autophagy. These findings reveal that autophagosomes associated with QC are molecularly and biochemically distinct from those associated with starvation autophagy, thereby providing a new molecular framework to understand the emerging complexity of autophagy and therapeutic potential of this unique machinery.
Lee
Joo-Yong
JY
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
Yao
Tso-Pang
TP
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
D018696:Neuroprotective Agents; D025801:Ubiquitin; D006655:Histone Deacetylases