The Machado–Joseph disease deubiquitylase ataxin‐3 interacts with LC3C/GABARAP and promotes autophagy

Abstract

The pathology of spinocerebellar ataxia type 3, also known as Machado‐Joseph disease, is triggered by aggregation of toxic ataxin‐3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX‐3, the nematode orthologue of ATXN3, together with the ubiquitin‐directed segregase CDC‐48, regulates longevity in Caenorhabditis elegans. Here, we demonstrate that the long‐lived cdc‐48.1; atx‐3 double mutant displays reduced viability under prolonged starvation conditions that can be attributed to the loss of catalytically active ATX‐3. Reducing the levels of the autophagy protein BEC‐1 sensitized worms to the effect of ATX‐3 deficiency, suggesting a role of ATX‐3 in autophagy. In support of this conclusion, the depletion of ATXN3 in human cells caused a reduction in autophagosomal degradation of proteins. Surprisingly, reduced degradation in ATXN3‐depleted cells coincided with an increase in the number of autophagosomes while levels of lipidated LC3 remained unaffected. We identified two conserved LIR domains in the catalytic Josephin domain of ATXN3 that directly interacted with the autophagy adaptors LC3C and GABARAP in vitro. While ATXN3 localized to early autophagosomes, it was not subject to lysosomal degradation, suggesting a transient regulatory interaction early in the autophagic pathway. We propose that the deubiquitylase ATX‐3/ATXN3 stimulates autophagic degradation by preventing superfluous initiation of autophagosomes, thereby promoting an efficient autophagic flux important to survive starvation.

The price of longevity

“…In line with these results, we indeed found a decrease in autophagy flux upon depletion of the human ATX-3 orthologue Ataxin-3 in cell culture models [ 5 ]. While Ataxin-3 deficient cells are still able to induce autophagy, the induction process appeared to be exaggerated with an increased number of autophagosomes, which is accompanied by less efficient turnover of proteins by autophagy.…”

“…This remarkable molecular interconnection raised questions about the functional status of the UPS and autophagy in these long-lived worms lacking CDC-48.1 and ATX-3. Our recent work resulted in the intriguing observation that the increased lifespan comes at a cost: while the cdc-48.1; atx-3 double mutant worms live longer they have to carry the burden of an increased sensitivity towards starvation [ 5 ]. This phenomenon suggests a defect in autophagy as this process is critical in recycling nutrients in the absence of food.…”

Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques

“…A weak binding of Ataxin-3 has also been detected with LC3A but its dependence on the LIR motif remains to be confirmed. Not only LC3B but also GABARAPL1/L2 seem not to bind Ataxin-3 (Herzog et al, 2019). TP53INP2 also shows a higher binding affinity for LC3C and GABARAPs compared to LC3A/B, but the molecular details underlying this preferential binding are still unclear (Atkinson et al, 2019).…”

Gelatine nanostructured lipid carrier encapsulated FGF15 inhibits autophagy and improves recovery in spinal cord injury

“…Autophagy participates in the regulation of many diseases including SCI. Autophagy is induced by a variety of stress stimuli, including endoplasmic reticulum stress, hypoxia, DNA damage, redox stress and mitochondrial damage 13,14 . Many therapeutic interventions in SCI use neurotrophic factors and are mainly focused on reducing the damage caused by excessive autophagy in the spinal cord cells.…”