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

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.

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

“…To this end, HDAC6 recruits cortactin via deacetylation, thereby promoting the formation of an F-actin network that supports autophagosomelysosome fusion. 3 Autophagy is an evolutionarily conserved, ubiquitous and multistep process, by which cytosolic material is sequestered in a doublelayered membrane, delivered to the lysosome for degradation and recycled to fuel cellular growth. 4 Autophagy starts with the formation of an isolation membrane, a double membrane structure also called phagophore, which then encapsulates cytoplasmatic cargo, seals to form the autophagosome and eventually fuses with lysosomes to generate autophagolysosomes, where the cargo is broken down into its constituent components.…”

Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

“…The double catalytic domain, a ubiquitin-binding domain, and a nuclear export-signal domain are functionally conserved in mouse and human HDAC6, mediating the same deacetylase, [27] . It has been documented that the ubiquitinbinding domain plays an important role in HDAC6-mediated autophagosome maturation and autophagosome-lysosome fusion [14,15] . In this study, human HDAC6 was selected for overexpression, as it could provide evidence relevant to the clinical treatment of ALS.…”

“…HDAC6 acts as a multivalent adapter to bind both ubiquitinated proteins and dynein motors, recruiting misfolded protein cargos to the autophagosomes along the microtubules [14] . It is worth pointing out that HDAC6 stimulates the fusion of autophagosomes to lysosomes and substrate degradation in neurons [15] . Several lines of evidence have documented that HDAC6 defi ciency leads to autophagosome maturation failure, protein aggregation, and neurodegeneration [15,33] .…”

“…Previous studies have reported that HDAC6 plays an important role in the process of autophagy [15] . To determine the effect of HDAC6 in this process, we used immunoblotting to determine the LC3-II turnover in the spinal cord of 120-day-old SOD1 G93A mice, and found that HDAC6 overexpression decreased the elevated LC3-II level by ~30.2% (Fig.…”

“…Furthermore, HDAC6 is a central component of the aggresome that promotes autophagy by inducing the fusion of autophagosomes to lysosomes and regulates the protective response to the formation of cytotoxic protein aggregates [15,16] . Accumulating evidence has shown that HDAC6-induced autophagy rescues neurons from degeneration in animal models of Huntington's disease, Alzheimer's disease, and Parkinson's disease [17,18] .…”