PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation

Publication type:
Journal article
Metadata:
Autoren
  • Julio C Corral-Serrano
  • Ideke JC Lamers
  • Jeroen van Reeuwijk
  • Lonneke Duijkers
  • Anita DM Hoogendoorn
  • Adem Yildirim
  • Nikoleta Argyrou
  • Renate AA Ruigrok
  • Stef JF Letteboer
  • Rossano Butcher
  • Max D van Essen
  • Sanae Sakami
  • Sylvia EC van Beersum
  • Krzysztof Palczewski
  • Michael E Cheetham
  • Qin Liu
  • Karsten Boldt
  • Uwe Wolfrum
  • Marius Ueffing
  • Alejandro Garanto
  • Ronald Roepman
  • Rob WJ Collin
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000531067600044&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1073/pnas.1903125117
Externe Identifier
  • Clarivate Analytics Document Solution ID: LK7UR
  • PubMed Identifier: 32312818
ISSN
0027-8424
Ausgabe der Veröffentlichung
18
Zeitschrift
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Schlüsselwörter
  • photoreceptor
  • cilium
  • outer segments
  • actin
  • retinitis pigmentosa
Paginierung
9922 - 9931
Datum der Veröffentlichung
2020
Status
Published
Titel
PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation
Sub types
  • Article
Ausgabe der Zeitschrift
117

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Significance</jats:title> <jats:p> The photoreceptor outer segments are primary cilia, modified for phototransduction by incorporation of stacked opsin-loaded membrane disks that are continuously regenerated. This process is disrupted in several types of inherited retinal dystrophy, but the driving force remained unclear. We show that C2orf71/PCARE (photoreceptor cilium actin regulator), associated with inherited retinal dystrophy subtype RP54, efficiently recruits the Arp2/3 complex activator WASF3 to the cilium. This activates an actin dynamics-driven expansion of the ciliary tip, resembling membrane evagination in lamellipodia formation. Colocalization of this actin dynamics module to the base of the outer segments, and absence thereof in <jats:italic>Pcare</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> mice, suggests PCARE-regulated actin dynamics as a critical process in outer segment disk formation. </jats:p>
Autoren
  • Julio C Corral-Serrano
  • Ideke JC Lamers
  • Jeroen van Reeuwijk
  • Lonneke Duijkers
  • Anita DM Hoogendoorn
  • Adem Yildirim
  • Nikoleta Argyrou
  • Renate AA Ruigrok
  • Stef JF Letteboer
  • Rossano Butcher
  • Max D van Essen
  • Sanae Sakami
  • Sylvia EC van Beersum
  • Krzysztof Palczewski
  • Michael E Cheetham
  • Qin Liu
  • Karsten Boldt
  • Uwe Wolfrum
  • Marius Ueffing
  • Alejandro Garanto
  • Ronald Roepman
  • Rob WJ Collin
DOI
10.1073/pnas.1903125117
eISSN
1091-6490
ISSN
0027-8424
Ausgabe der Veröffentlichung
18
Zeitschrift
Proceedings of the National Academy of Sciences
Sprache
en
Online publication date
2020
Paginierung
9922 - 9931
Datum der Veröffentlichung
2020
Status
Published
Herausgeber
Proceedings of the National Academy of Sciences
Herausgeber URL
http://dx.doi.org/10.1073/pnas.1903125117
Datum der Datenerfassung
2022
Titel
PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation
Ausgabe der Zeitschrift
117

Data source: Crossref

Abstract
The outer segments (OS) of rod and cone photoreceptor cells are specialized sensory cilia that contain hundreds of opsin-loaded stacked membrane disks that enable phototransduction. The biogenesis of these disks is initiated at the OS base, but the driving force has been debated. Here, we studied the function of the protein encoded by the photoreceptor-specific gene <i>C2orf71</i>, which is mutated in inherited retinal dystrophy (RP54). We demonstrate that C2orf71/PCARE (photoreceptor cilium actin regulator) can interact with the Arp2/3 complex activator WASF3, and efficiently recruits it to the primary cilium. Ectopic coexpression of PCARE and WASF3 in ciliated cells results in the remarkable expansion of the ciliary tip. This process was disrupted by small interfering RNA (siRNA)-based down-regulation of an actin regulator, by pharmacological inhibition of actin polymerization, and by the expression of PCARE harboring a retinal dystrophy-associated missense mutation. Using human retinal organoids and mouse retina, we observed that a similar actin dynamics-driven process is operational at the base of the photoreceptor OS where the PCARE module and actin colocalize, but which is abrogated in <i>Pcare</i><sup><i>-/-</i></sup> mice. The observation that several proteins involved in retinal ciliopathies are translocated to these expansions renders it a potential common denominator in the pathomechanisms of these hereditary disorders. Together, our work suggests that PCARE is an actin-associated protein that interacts with WASF3 to regulate the actin-driven expansion of the ciliary membrane at the initiation of new outer segment disk formation.
Addresses
  • Department of Human Genetics, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.
Autoren
  • Julio C Corral-Serrano
  • Ideke JC Lamers
  • Jeroen van Reeuwijk
  • Lonneke Duijkers
  • Anita DM Hoogendoorn
  • Adem Yildirim
  • Nikoleta Argyrou
  • Renate AA Ruigrok
  • Stef JF Letteboer
  • Rossano Butcher
  • Max D van Essen
  • Sanae Sakami
  • Sylvia EC van Beersum
  • Krzysztof Palczewski
  • Michael E Cheetham
  • Qin Liu
  • Karsten Boldt
  • Uwe Wolfrum
  • Marius Ueffing
  • Alejandro Garanto
  • Ronald Roepman
  • Rob WJ Collin
DOI
10.1073/pnas.1903125117
eISSN
1091-6490
Externe Identifier
  • PubMed Identifier: 32312818
  • PubMed Central ID: PMC7211956
Funding acknowledgements
  • NEI NIH HHS: R01 EY009339
  • Dutch Research Council (NWO): 865.12.005
  • ZonMw: 91216051
  • Foundation Fighting Blindness: PPA-0717-0719-RAD
  • Dutch Research Council (NWO): NWO Vici-865.12.005
  • European Community&apos;s Seventh Framework FP7/2009 programme SYSCILIA: 241955
  • FP7-PEOPLE-2012-ITN: 317472
  • Wellcome Trust: 205041/Z/16/Z
  • The Netherlands Organization for Health Research and Development: ZonMW-91216051
Open access
true
ISSN
0027-8424
Ausgabe der Veröffentlichung
18
Zeitschrift
Proceedings of the National Academy of Sciences of the United States of America
Schlüsselwörter
  • Cilia
  • Animals
  • Mice, Knockout
  • Humans
  • Mice
  • Disease Models, Animal
  • Actins
  • Eye Proteins
  • RNA, Small Interfering
  • Gene Expression Regulation
  • Wiskott-Aldrich Syndrome Protein Family
  • Actin-Related Protein 2-3 Complex
  • Rod Cell Outer Segment
  • Retinal Cone Photoreceptor Cells
  • Cone-Rod Dystrophies
Sprache
eng
Medium
Print-Electronic
Online publication date
2020
Open access status
Open Access
Paginierung
9922 - 9931
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2020
Titel
PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
117

Files

https://www.pnas.org/content/pnas/117/18/9922.full.pdf https://europepmc.org/articles/PMC7211956?pdf=render

Data source: Europe PubMed Central

Abstract
The outer segments (OS) of rod and cone photoreceptor cells are specialized sensory cilia that contain hundreds of opsin-loaded stacked membrane disks that enable phototransduction. The biogenesis of these disks is initiated at the OS base, but the driving force has been debated. Here, we studied the function of the protein encoded by the photoreceptor-specific gene C2orf71, which is mutated in inherited retinal dystrophy (RP54). We demonstrate that C2orf71/PCARE (photoreceptor cilium actin regulator) can interact with the Arp2/3 complex activator WASF3, and efficiently recruits it to the primary cilium. Ectopic coexpression of PCARE and WASF3 in ciliated cells results in the remarkable expansion of the ciliary tip. This process was disrupted by small interfering RNA (siRNA)-based down-regulation of an actin regulator, by pharmacological inhibition of actin polymerization, and by the expression of PCARE harboring a retinal dystrophy-associated missense mutation. Using human retinal organoids and mouse retina, we observed that a similar actin dynamics-driven process is operational at the base of the photoreceptor OS where the PCARE module and actin colocalize, but which is abrogated in Pcare-/- mice. The observation that several proteins involved in retinal ciliopathies are translocated to these expansions renders it a potential common denominator in the pathomechanisms of these hereditary disorders. Together, our work suggests that PCARE is an actin-associated protein that interacts with WASF3 to regulate the actin-driven expansion of the ciliary membrane at the initiation of new outer segment disk formation.
Autoren
  • Julio C Corral-Serrano
  • Ideke JC Lamers
  • Jeroen van Reeuwijk
  • Lonneke Duijkers
  • Anita DM Hoogendoorn
  • Adem Yildirim
  • Nikoleta Argyrou
  • Renate AA Ruigrok
  • Stef JF Letteboer
  • Rossano Butcher
  • Max D van Essen
  • Sanae Sakami
  • Sylvia EC van Beersum
  • Krzysztof Palczewski
  • Michael E Cheetham
  • Qin Liu
  • Karsten Boldt
  • Uwe Wolfrum
  • Marius Ueffing
  • Alejandro Garanto
  • Ronald Roepman
  • Rob WJ Collin
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/32312818
DOI
10.1073/pnas.1903125117
eISSN
1091-6490
Externe Identifier
  • PubMed Central ID: PMC7211956
Funding acknowledgements
  • Wellcome Trust: 205041/Z/16/Z
  • NEI NIH HHS: R01 EY009339
Ausgabe der Veröffentlichung
18
Zeitschrift
Proc Natl Acad Sci U S A
Schlüsselwörter
  • actin
  • cilium
  • outer segments
  • photoreceptor
  • retinitis pigmentosa
  • Actin-Related Protein 2-3 Complex
  • Actins
  • Animals
  • Cilia
  • Cone-Rod Dystrophies
  • Disease Models, Animal
  • Eye Proteins
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • RNA, Small Interfering
  • Retinal Cone Photoreceptor Cells
  • Rod Cell Outer Segment
  • Wiskott-Aldrich Syndrome Protein Family
Sprache
eng
Country
United States
Paginierung
9922 - 9931
PII
1903125117
Datum der Veröffentlichung
2020
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2020
Titel
PCARE and WASF3 regulate ciliary F-actin assembly that is required for the initiation of photoreceptor outer segment disk formation.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
117

Data source: PubMed

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