Universität zu Köln

Herzog, Laura K., Kevei, Eva ORCID: 0000-0002-0560-9208, Marchante, Ricardo, Bottcher, Claudia, Bindesboll, Christian, Lystad, Alf Hakon ORCID: 0000-0002-5606-3276, Pfeiffer, Annika ORCID: 0000-0002-0340-5797, Gierisch, Maria E., Salomons, Florian A., Simonsen, Anne, Hoppe, Thorsten ORCID: 0000-0002-4734-9352 and Dantuma, Nico P. (2020). The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy. Aging Cell, 19 (1). HOBOKEN: WILEY. ISSN 1474-9726

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Herzog, Laura K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kevei, Eva UNSPECIFIED orcid.org/0000-0002-0560-9208 UNSPECIFIED Marchante, Ricardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Bottcher, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bindesboll, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Lystad, Alf Hakon UNSPECIFIED orcid.org/0000-0002-5606-3276 UNSPECIFIED Pfeiffer, Annika UNSPECIFIED orcid.org/0000-0002-0340-5797 UNSPECIFIED Gierisch, Maria E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salomons, Florian A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Simonsen, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED Dantuma, Nico P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-130741
DOI:	10.1111/acel.13051
Journal or Publication Title:	Aging Cell
Volume:	19
Number:	1
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1474-9726
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEUBIQUITINATING ENZYME; RETROTRANSLOCATION; NEURODEGENERATION; EXPANSIONS; DROSOPHILA; TOXICITY; PROTEINS; VCP/P97; ELEGANS; GENE Multiple languages Cell Biology; Geriatrics & Gerontology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13074