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

Ataxin-7 (Atxn7), a subunit of the 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 amino terminus of Atxn7 anchors the Non-stop deubiquitinase to the complex. To understand the consequences of Atxn7-dependent regulation of Non-stop, we sought substrates for Non-stop and discovered the deubiquitinase, dissociated from SAGA, interacts with Arp2/3 and WAVE regulatory complexes (WRC). Protein levels of WRC subunit suppressor of extracellular cAMP receptor (cAR) (SCAR) are regulated by a constant ubiquitination/proteasomal degradation mechanism. Loss of Atxn7 frees Non-stop from SAGA, leading to increased Non-stop interaction with SCAR and also increased SCAR protein levels. A Non-stop enzymatic pocket mutation that increases binding to ubiquitin increased interaction with SCAR, while an enzymatic pocket mutation reducing binding to ubiquitin also reduced binding to SCAR. Loss of Non-stop increased polyubiquitination of SCAR and reduced SCAR protein levels although SCAR protein levels were rescued by protease inhibition. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop overexpression increased SCAR protein levels and directed subcellular localization of SCAR, leading to decreased cell area and decreased number of protrusions. In vivo , heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR to produce F actin, but heterozygous mutation of SCAR did not significantly rescue retinal axon mistargeting upon knockdown of Atxn7. Summary SAGA subunits Ataxin-7 and Non-stop regulate stability and subcellular localization of WRC subunit SCAR. Loss of Ataxin-7 increases, while loss of Non-stop decreases, SCAR protein levels and F-actin network assembly.

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