Multiple ciliary localization signals control INPP5E ciliary targeting
Primary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in cilia remains poorly understood. Herein, we sho...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-09-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/78383 |
| _version_ | 1811181214577459200 |
|---|---|
| author | Dario Cilleros-Rodriguez Raquel Martin-Morales Pablo Barbeito Abhijit Deb Roy Abdelhalim Loukil Belen Sierra-Rodero Gonzalo Herranz Olatz Pampliega Modesto Redrejo-Rodriguez Sarah C Goetz Manuel Izquierdo Takanari Inoue Francesc R Garcia-Gonzalo |
| author_facet | Dario Cilleros-Rodriguez Raquel Martin-Morales Pablo Barbeito Abhijit Deb Roy Abdelhalim Loukil Belen Sierra-Rodero Gonzalo Herranz Olatz Pampliega Modesto Redrejo-Rodriguez Sarah C Goetz Manuel Izquierdo Takanari Inoue Francesc R Garcia-Gonzalo |
| author_sort | Dario Cilleros-Rodriguez |
| collection | DOAJ |
| description | Primary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in cilia remains poorly understood. Herein, we show INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four conserved ciliary localization signals (CLSs): LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial CLS1-CLS4 redundancy explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 clarifies why CLS3-CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations perturb INPP5E ciliary targeting, and clarify how each CLS works: (i) CLS4 recruits PDE6D, RPGR and ARL13B, (ii) CLS2-CLS3 regulate association to TULP3, ARL13B, and CEP164, and (iii) CLS1 and CLS4 cooperate in ATG16L1 binding. Altogether, we shed light on the mechanisms of INPP5E ciliary targeting, revealing a complexity without known parallels among ciliary cargoes. |
| first_indexed | 2024-04-11T09:15:22Z |
| format | Article |
| id | doaj.art-cfd0cf2219bf4640ab9dff7407cfa7b3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:15:22Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-cfd0cf2219bf4640ab9dff7407cfa7b32022-12-22T04:32:23ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.78383Multiple ciliary localization signals control INPP5E ciliary targetingDario Cilleros-Rodriguez0https://orcid.org/0000-0001-9529-5320Raquel Martin-Morales1https://orcid.org/0000-0003-0933-6160Pablo Barbeito2https://orcid.org/0000-0003-0758-0012Abhijit Deb Roy3https://orcid.org/0000-0003-1640-2402Abdelhalim Loukil4Belen Sierra-Rodero5Gonzalo Herranz6Olatz Pampliega7https://orcid.org/0000-0002-7924-6374Modesto Redrejo-Rodriguez8Sarah C Goetz9https://orcid.org/0000-0001-9705-6390Manuel Izquierdo10https://orcid.org/0000-0002-7701-1002Takanari Inoue11https://orcid.org/0000-0002-7957-7624Francesc R Garcia-Gonzalo12https://orcid.org/0000-0002-9152-2191Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartment of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United StatesDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, SpainDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, SpainDepartment of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Leioa, SpainDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, SpainDepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United StatesDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, SpainDepartment of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, United StatesDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, SpainPrimary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in cilia remains poorly understood. Herein, we show INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four conserved ciliary localization signals (CLSs): LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial CLS1-CLS4 redundancy explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 clarifies why CLS3-CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations perturb INPP5E ciliary targeting, and clarify how each CLS works: (i) CLS4 recruits PDE6D, RPGR and ARL13B, (ii) CLS2-CLS3 regulate association to TULP3, ARL13B, and CEP164, and (iii) CLS1 and CLS4 cooperate in ATG16L1 binding. Altogether, we shed light on the mechanisms of INPP5E ciliary targeting, revealing a complexity without known parallels among ciliary cargoes.https://elifesciences.org/articles/78383ciliaciliopathiesJoubert syndromeINPP5Ephosphoinositidesphosphatase |
| spellingShingle | Dario Cilleros-Rodriguez Raquel Martin-Morales Pablo Barbeito Abhijit Deb Roy Abdelhalim Loukil Belen Sierra-Rodero Gonzalo Herranz Olatz Pampliega Modesto Redrejo-Rodriguez Sarah C Goetz Manuel Izquierdo Takanari Inoue Francesc R Garcia-Gonzalo Multiple ciliary localization signals control INPP5E ciliary targeting eLife cilia ciliopathies Joubert syndrome INPP5E phosphoinositides phosphatase |
| title | Multiple ciliary localization signals control INPP5E ciliary targeting |
| title_full | Multiple ciliary localization signals control INPP5E ciliary targeting |
| title_fullStr | Multiple ciliary localization signals control INPP5E ciliary targeting |
| title_full_unstemmed | Multiple ciliary localization signals control INPP5E ciliary targeting |
| title_short | Multiple ciliary localization signals control INPP5E ciliary targeting |
| title_sort | multiple ciliary localization signals control inpp5e ciliary targeting |
| topic | cilia ciliopathies Joubert syndrome INPP5E phosphoinositides phosphatase |
| url | https://elifesciences.org/articles/78383 |
| work_keys_str_mv | AT dariocillerosrodriguez multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT raquelmartinmorales multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT pablobarbeito multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT abhijitdebroy multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT abdelhalimloukil multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT belensierrarodero multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT gonzaloherranz multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT olatzpampliega multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT modestoredrejorodriguez multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT sarahcgoetz multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT manuelizquierdo multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT takanariinoue multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting AT francescrgarciagonzalo multipleciliarylocalizationsignalscontrolinpp5eciliarytargeting |