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The Machado-Joseph Disease Deubiquitylase ataxin-3 Interacts With LC3C/GABARAP and Promotes Autophagy

The Machado-Joseph Disease Deubiquitylase ataxin-3 Interacts With LC3C/GABARAP and Promotes Autophagy

Laura K Herzog, Éva Kevei, Ricardo Marchante, Claudia Böttcher, Christian Bindesbøll, Alf Håkon Lystad, Annika Pfeiffer, Maria E Gierisch, Florian A Salomons, Anne Simonsen, Thorsten Hoppe, Nico P Dantuma

Aging Cell. 2020 Jan;19(1):e13051.

PMID: 31625269

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415051	Ataxin3 active human			Price

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