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A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation

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...

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Autores principales: Huang, Timothy Y., Michael, Sarah, Xu, Tao, Sarkeshik, Ali, Moresco, James J., Yates, John R., Masliah, Eliezer, Bokoch, Gary M., DerMardirossian, Céline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564530/
https://www.ncbi.nlm.nih.gov/pubmed/23223568
http://dx.doi.org/10.1091/mbc.E12-07-0565
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author Huang, Timothy Y.
Michael, Sarah
Xu, Tao
Sarkeshik, Ali
Moresco, James J.
Yates, John R.
Masliah, Eliezer
Bokoch, Gary M.
DerMardirossian, Céline
author_facet Huang, Timothy Y.
Michael, Sarah
Xu, Tao
Sarkeshik, Ali
Moresco, James J.
Yates, John R.
Masliah, Eliezer
Bokoch, Gary M.
DerMardirossian, Céline
author_sort Huang, Timothy Y.
collection PubMed
description 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.
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spelling pubmed-35645302013-04-16 A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation Huang, Timothy Y. Michael, Sarah Xu, Tao Sarkeshik, Ali Moresco, James J. Yates, John R. Masliah, Eliezer Bokoch, Gary M. DerMardirossian, Céline Mol Biol Cell Articles 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. The American Society for Cell Biology 2013-02-01 /pmc/articles/PMC3564530/ /pubmed/23223568 http://dx.doi.org/10.1091/mbc.E12-07-0565 Text en © 2013 Huang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Huang, Timothy Y.
Michael, Sarah
Xu, Tao
Sarkeshik, Ali
Moresco, James J.
Yates, John R.
Masliah, Eliezer
Bokoch, Gary M.
DerMardirossian, Céline
A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title_full A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title_fullStr A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title_full_unstemmed A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title_short A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
title_sort novel rac1 gap splice variant relays poly-ub accumulation signals to mediate rac1 inactivation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564530/
https://www.ncbi.nlm.nih.gov/pubmed/23223568
http://dx.doi.org/10.1091/mbc.E12-07-0565
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