title: ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Humbert
authors.forename: Katie
authors.initials: K
authors.lastname: Weihbrecht
authors.forename: Charles C
authors.initials: CC
authors.lastname: Searby
authors.forename: Yalan
authors.initials: Y
authors.lastname: Li
authors.forename: Robert M
authors.initials: RM
authors.lastname: Pope
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Seongjin
authors.initials: S
authors.lastname: Seo
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002924:Ciliary Body / Q000502:physiology*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000502:physiology*; D006801:Humans; D008868:Microtubule Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D020727:ADP-Ribosylation Factors; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D008868:Microtubule Proteins; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C524694:CEP164 protein, human; C517432:PDE6D protein, human; C530391:ARL13B protein, human