Ataxin-7 and Non-stop coordinate SCAR protein levels, subcellular localization, and actin cytoskeleton organization

• Published in: eLife Vol. 8
• Main Authors: Cloud, Veronica, Thapa, Ada, Morales-Sosa, Pedro, Miller, Tayla M, Miller, Sara A, Holsapple, Daniel, Gerhart, Paige M, Momtahan, Elaheh, Jack, Jarrid L, Leiva, Edgardo, Rapp, Sarah R, Shelton, Lauren G, Pierce, Richard A, Martin-Brown, Skylar, Florens, Laurence, Washburn, Michael P, Mohan, Ryan D
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26.07.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Actin; Actin Cytoskeleton - metabolism; Animals; Ataxia; Ataxin; Ataxin-7 - metabolism; Ataxin7; Cell Biology; Chromatin; Chromatin remodeling; Cytoskeleton; Disease; Drosophila melanogaster - physiology; Drosophila Proteins - metabolism; Endopeptidases - metabolism; Enzymes; Gene expression; Gene Expression Regulation; Genotype & phenotype; Haploinsufficiency; Insects; Localization; Mass spectrometry; Microfilament Proteins - metabolism; Mutation; Nervous system diseases; neurobiology; Neurodegeneration; Neurodegenerative diseases; Neuroscience; Non-stop; Peptides; Physiological aspects; Polyglutamine; Proteasomes; Protein Interaction Mapping; Protein Interaction Maps; Proteins; Retina; SAGA complex; Scientific imaging; Spinocerebellar ataxia; Spinocerebellar ataxias; Trinucleotide repeat diseases; WAVE regulatory complex; France; United States > US; Kansas City Missouri; actin; cell biology; Non-stop; neuroscience; WAVE regulatory complex; neurobiology; D. melanogaster; SAGA complex; Ataxin7
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.49677

Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7, but heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR.