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A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1

Primary cilia regulate epithelial differentiation and organ function. Failure of mutant polycystins to localize to cilia abolishes flow-stimulated calcium signaling and causes autosomal dominant polycystic kidney disease. We identify a conserved amino acid sequence, KVHPSST, in the C-terminus of pol...

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Autores principales: Ward, Heather H., Brown-Glaberman, Ursa, Wang, Jing, Morita, Yoshiko, Alper, Seth L., Bedrick, Edward J., Gattone, Vincent H., Deretic, Dusanka, Wandinger-Ness, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172256/
https://www.ncbi.nlm.nih.gov/pubmed/21775626
http://dx.doi.org/10.1091/mbc.E11-01-0082
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author Ward, Heather H.
Brown-Glaberman, Ursa
Wang, Jing
Morita, Yoshiko
Alper, Seth L.
Bedrick, Edward J.
Gattone, Vincent H.
Deretic, Dusanka
Wandinger-Ness, Angela
author_facet Ward, Heather H.
Brown-Glaberman, Ursa
Wang, Jing
Morita, Yoshiko
Alper, Seth L.
Bedrick, Edward J.
Gattone, Vincent H.
Deretic, Dusanka
Wandinger-Ness, Angela
author_sort Ward, Heather H.
collection PubMed
description Primary cilia regulate epithelial differentiation and organ function. Failure of mutant polycystins to localize to cilia abolishes flow-stimulated calcium signaling and causes autosomal dominant polycystic kidney disease. We identify a conserved amino acid sequence, KVHPSST, in the C-terminus of polycystin-1 (PC1) that serves as a ciliary-targeting signal. PC1 binds a multimeric protein complex consisting of several GTPases (Arf4, Rab6, Rab11) and the GTPase-activating protein (GAP), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) in the Golgi, which facilitates vesicle budding and Golgi exocytosis. A related N-terminal ciliary-targeting sequence in polycystin-2 similarly binds Arf4. Deletion of the extreme C-terminus of PC1 ablates Arf4 and ASAP1 binding and prevents ciliary localization of an integral membrane CD16.7-PC1 chimera. Interactions are confirmed for chimeric and endogenous proteins through quantitated in vitro and cell-based approaches. PC1 also complexes with Rab8; knockdown of trafficking regulators Arf4 or Rab8 functionally blocks CD16.7-PC1 trafficking to cilia. Mutations in rhodopsin disrupt a similar signal and cause retinitis pigmentosa, while Bardet-Biedl syndrome, primary open-angle glaucoma, and tumor cell invasiveness are linked to dysregulation of ASAP1 or Rab8 or its effectors. In this paper, we provide evidence for a conserved GTPase-dependent ciliary-trafficking mechanism that is shared between epithelia and neurons, and is essential in ciliary-trafficking and cell homeostasis.
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spelling pubmed-31722562011-11-30 A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1 Ward, Heather H. Brown-Glaberman, Ursa Wang, Jing Morita, Yoshiko Alper, Seth L. Bedrick, Edward J. Gattone, Vincent H. Deretic, Dusanka Wandinger-Ness, Angela Mol Biol Cell Articles Primary cilia regulate epithelial differentiation and organ function. Failure of mutant polycystins to localize to cilia abolishes flow-stimulated calcium signaling and causes autosomal dominant polycystic kidney disease. We identify a conserved amino acid sequence, KVHPSST, in the C-terminus of polycystin-1 (PC1) that serves as a ciliary-targeting signal. PC1 binds a multimeric protein complex consisting of several GTPases (Arf4, Rab6, Rab11) and the GTPase-activating protein (GAP), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) in the Golgi, which facilitates vesicle budding and Golgi exocytosis. A related N-terminal ciliary-targeting sequence in polycystin-2 similarly binds Arf4. Deletion of the extreme C-terminus of PC1 ablates Arf4 and ASAP1 binding and prevents ciliary localization of an integral membrane CD16.7-PC1 chimera. Interactions are confirmed for chimeric and endogenous proteins through quantitated in vitro and cell-based approaches. PC1 also complexes with Rab8; knockdown of trafficking regulators Arf4 or Rab8 functionally blocks CD16.7-PC1 trafficking to cilia. Mutations in rhodopsin disrupt a similar signal and cause retinitis pigmentosa, while Bardet-Biedl syndrome, primary open-angle glaucoma, and tumor cell invasiveness are linked to dysregulation of ASAP1 or Rab8 or its effectors. In this paper, we provide evidence for a conserved GTPase-dependent ciliary-trafficking mechanism that is shared between epithelia and neurons, and is essential in ciliary-trafficking and cell homeostasis. The American Society for Cell Biology 2011-09-15 /pmc/articles/PMC3172256/ /pubmed/21775626 http://dx.doi.org/10.1091/mbc.E11-01-0082 Text en © 2011 Ward 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
Ward, Heather H.
Brown-Glaberman, Ursa
Wang, Jing
Morita, Yoshiko
Alper, Seth L.
Bedrick, Edward J.
Gattone, Vincent H.
Deretic, Dusanka
Wandinger-Ness, Angela
A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title_full A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title_fullStr A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title_full_unstemmed A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title_short A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1
title_sort conserved signal and gtpase complex are required for the ciliary transport of polycystin-1
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172256/
https://www.ncbi.nlm.nih.gov/pubmed/21775626
http://dx.doi.org/10.1091/mbc.E11-01-0082
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