ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

Melissa C Humbert; Katie Weihbrecht; Charles C Searby; Yalan Li; Robert M Pope; Val C Sheffield; Seongjin Seo

doi:10.1073/pnas.1210916109

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ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

Journal article

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Peer reviewed

ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting

Melissa C Humbert, Katie Weihbrecht, Charles C Searby, Yalan Li, Robert M Pope, Val C Sheffield and Seongjin Seo

Proceedings of the National Academy of Sciences - PNAS, Vol.109(48), pp.19691-19696

11/27/2012

DOI: 10.1073/pnas.1210916109

PMCID: PMC3511769

PMID: 23150559

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Abstract

Mutations affecting ciliary components cause a series of related genetic disorders in humans, including nephronophthisis (NPHP), Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS), which are collectively termed "ciliopathies." Recent protein-protein interaction studies combined with genetic analyses revealed that ciliopathy-related proteins form several functional networks/modules that build and maintain the primary cilium. However, the precise function of many ciliopathy-related proteins and the mechanisms by which these proteins are targeted to primary cilia are still not well understood. Here, we describe a protein-protein interaction network of inositol polyphosphate-5-phosphatase E (INPP5E), a prenylated protein associated with JBTS, and its ciliary targeting mechanisms. INPP5E is targeted to the primary cilium through a motif near the C terminus and prenyl-binding protein phosphodiesterase 6D (PDE6D)-dependent mechanisms. Ciliary targeting of INPP5E is facilitated by another JBTS protein, ADP-ribosylation factor-like 13B (ARL13B), but not by ARL2 or ARL3. ARL13B missense mutations that cause JBTS in humans disrupt the ARL13B-INPP5E interaction. We further demonstrate interactions of INPP5E with several ciliary and centrosomal proteins, including a recently identified ciliopathy protein centrosomal protein 164 (CEP164). These findings indicate that ARL13B, INPP5E, PDE6D, and CEP164 form a distinct functional network that is involved in JBTS and NPHP but independent of the ones previously defined by NPHP and MKS proteins.

Ciliary Body - physiology

Amino Acid Sequence

Humans

Microtubule Proteins - physiology

Molecular Sequence Data

Mutation, Missense

Phosphoric Monoester Hydrolases - physiology

Cyclic Nucleotide Phosphodiesterases, Type 6 - physiology

Sequence Homology, Amino Acid

Animals

ADP-Ribosylation Factors - physiology

ADP-Ribosylation Factors - genetics

Phosphoric Monoester Hydrolases - chemistry

Details

Title: Subtitle: ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting
Creators: Melissa C Humbert - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA
Katie Weihbrecht
Charles C Searby
Yalan Li - University of Iowa
Robert M Pope
Val C Sheffield
Seongjin Seo
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.109(48), pp.19691-19696
DOI: 10.1073/pnas.1210916109
PMID: 23150559
PMCID: PMC3511769
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 1091-6490
eISSN: 1091-6490
Publisher: United States
Grant note: R01EY022616 / NEI NIH HHS R01EY017168 / NEI NIH HHS R01EY110298 / NEI NIH HHS R01 EY022616 / NEI NIH HHS Howard Hughes Medical Institute R01 EY017168 / NEI NIH HHS
Language: English
Date published: 11/27/2012
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medical Genetics and Genomics; Medicine Administration; Ophthalmology and Visual Sciences
Record Identifier: 9983979960002771

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