title: A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation.
abstract: Spatial control of RhoGTPase-inactivating GAP components remains largely enigmatic. We describe a brain-specific RhoGAP splice variant, BARGIN (BGIN), which comprises a combination of BAR, GAP, and partial CIN phosphatase domains spliced from adjacent SH3BP1 and CIN gene loci. Excision of BGIN exon 2 results in recoding of a 42-amino acid N-terminal stretch. The partial CIN domain is a poly-ubiquitin (poly-Ub)-binding module that facilitates BGIN distribution to membranous and detergent-insoluble fractions. Poly-Ub/BGIN interactions support BGIN-mediated inactivation of a membranous Rac1 population, which consequently inactivates membrane-localized Rac1 effector systems such as reactive oxygen species (ROS) generation by the Nox1 complex. Given that Ub aggregate pathology and proteotoxicity are central themes in various neurodegenerative disorders, we investigated whether BGIN/Rac1 signaling could be involved in neurodegenerative proteotoxicity. BGIN/Ub interactions are observed through colocalization in tangle aggregates in the Alzheimer's disease (AD) brain. Moreover, enhanced BGIN membrane distribution correlates with reduced Rac1 activity in AD brain tissue. Finally, BGIN contributes to Rac1 inhibition and ROS generation in an amyloid precursor protein (APP) proteotoxicity model. These results suggest that BGIN/poly-Ub interactions enhance BGIN membrane distribution and relay poly-Ub signals to enact Rac1 inactivation, and attenuation of Rac1 signaling is partially dependent on BGIN in a proteotoxic APP context.
authors.affiliation: Department of Immunobiology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Timothy Y
authors.initials: TY
authors.lastname: Huang
authors.forename: Sarah
authors.initials: S
authors.lastname: Michael
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Ali
authors.initials: A
authors.lastname: Sarkeshik
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch
authors.forename: Céline
authors.initials: C
authors.lastname: DerMardirossian
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000201:enzymology; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008969:Molecular Sequence Data; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D020690:GTPase-Activating Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D020033:Protein Isoforms; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C576051:SH3BP1 protein, human; D025821:Polyubiquitin; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C027138:pyridoxine phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde