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Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting

Dario Cilleros-Rodriguez, View ORCID ProfileRaquel Martin-Morales, View ORCID ProfilePablo Barbeito, View ORCID ProfileAbhijit Deb Roy, Abdelhalim Loukil, View ORCID ProfileBelen Sierra-Rodero, Gonzalo Herranz, View ORCID ProfileOlatz Pampliega, View ORCID ProfileModesto Redrejo-Rodriguez, View ORCID ProfileSarah C. Goetz, View ORCID ProfileManuel Izquierdo, View ORCID ProfileTakanari Inoue, View ORCID ProfileFrancesc R. Garcia-Gonzalo
doi: https://doi.org/10.1101/2022.01.25.477585
Dario Cilleros-Rodriguez
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
3Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain
4CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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Raquel Martin-Morales
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
3Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain
4CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • ORCID record for Raquel Martin-Morales
Pablo Barbeito
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
3Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain
4CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • ORCID record for Pablo Barbeito
Abhijit Deb Roy
5Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Abdelhalim Loukil
6Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA
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Belen Sierra-Rodero
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
3Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain
4CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • ORCID record for Belen Sierra-Rodero
Gonzalo Herranz
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
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Olatz Pampliega
7Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Leioa, Spain
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Modesto Redrejo-Rodriguez
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
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Sarah C. Goetz
6Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA
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Manuel Izquierdo
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
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Takanari Inoue
5Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Francesc R. Garcia-Gonzalo
1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain
2Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), Consejo Superior de Investigaciones Científicas (CSIC)-UAM, Madrid, Spain
3Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain
4CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • For correspondence: francesc.garcia@uam.es
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ABSTRACT

Primary cilia are sensory membrane protrusions whose dysfunction causes diseases named ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, such as cilium stability, trafficking, signaling, or exovesicle release. Despite its key ciliary roles, how INPP5E accumulates in cilia remains poorly understood. Herein, we show that INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four ciliary localization signals (CLSs), the first two of which we newly discover: LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial redundancy between CLS1 and CLS4 explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 on the catalytic domain surface clarifies why CLS3 and CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations in INPP5E catalytic domain affect its ciliary targeting, and shed light on the mechanisms of action of each CLS. Thus, we find that CLS2 and CLS3 promote interaction with TULP3 and ARL13B, while downregulating CEP164 binding. On the other hand, CLS4 recruits PDE6D, RPGR and ARL13B, and cooperates with CLS1 in ATG16L1 binding. Lastly, we show INPP5E immune synapse targeting is CLS-independent. Altogether, we reveal unusual complexity in INPP5E ciliary targeting mechanisms, likely reflecting its multiple key roles in ciliary biology.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 26, 2022.
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Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting
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
bioRxiv 2022.01.25.477585; doi: https://doi.org/10.1101/2022.01.25.477585
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Multiple Ciliary Localization Signals Control INPP5E Ciliary Targeting
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
bioRxiv 2022.01.25.477585; doi: https://doi.org/10.1101/2022.01.25.477585

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