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      BBS1 is involved in retrograde trafficking of ciliary GPCRs in the context of the BBSome complex

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      PLoS ONE
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          Abstract

          Protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery composed of large protein complexes. The BBSome consists of eight BBS proteins encoded by causative genes of Bardet-Biedl syndrome (BBS), and has been implicated in the trafficking of ciliary membrane proteins, including G protein-coupled receptors (GPCRs), by connecting the IFT machinery to cargo GPCRs. Membrane recruitment of the BBSome to promote cargo trafficking has been proposed to be regulated by the Arf-like small GTPase ARL6/BBS3, through its interaction with the BBS1 subunit of the BBSome. We here investigated how the BBSome core subcomplex composed of BBS1, BBS2, BBS7, and BBS9 assembles and interacts with ARL6, and found that the ARL6–BBS1 interaction is reinforced by BBS9. BBS1-knockout (KO) cells showed defects in the ciliary entry of other BBSome subunits and ARL6, and in ciliary retrograde trafficking and the export of the GPCRs, Smoothened and GPR161. The trafficking defect of these GPCRs was rescued by the exogenous expression of wild-type BBS1, but not by its mutant lacking BBS9-binding ability. Our data thus indicate that the intact BBSome is required for retrograde trafficking of GPCRs out of cilia.

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          Most cited references21

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          Rab11 regulates exocytosis of recycling vesicles at the plasma membrane.

          Rab11 is known to associate primarily with perinuclear recycling endosomes and regulate recycling of endocytosed proteins. However, the recycling step in which Rab11 participates remains unknown. We show here that, in addition to causing tubulation of recycling endosomes, Rab11 depletion gives rise to accumulation of recycling carriers containing endocytosed transferrin and transferrin receptor beneath the plasma membrane. We also show that the carriers are transported from perinuclear recycling endosomes to the cell periphery along microtubules. Total internal reflection fluorescence microscopy of cells expressing EGFP-tagged transferrin receptor revealed that Rab11 depletion inhibits tethering and fusion of recycling carriers to the plasma membrane. Depletion of Sec15, which interacts with Rab11, or Exo70, both components of the exocyst tethering complex, leads to essentially the same phenotypes as those of Rab11 depletion. Thus, in addition to its role in recycling processes at perinuclear recycling endosomes, Rab11 is transported along microtubules to the cell periphery through association with recycling carriers, and directly regulates vesicle exocytosis at the plasma membrane in concert with the exocyst.
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            IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment.

            Vertebrate hedgehog signaling is coordinated by the differential localization of the receptors patched-1 and Smoothened in the primary cilium. Cilia assembly is mediated by intraflagellar transport (IFT), and cilia defects disrupt hedgehog signaling, causing many structural birth defects. We generated Ift25 and Ift27 knockout mice and show that they have structural birth defects indicative of hedgehog signaling dysfunction. Surprisingly, ciliary assembly is not affected, but abnormal hedgehog signaling is observed in conjunction with ciliary accumulation of patched-1 and Smoothened. Similarly, Smoothened accumulates in cilia on cells mutated for BBSome components or the BBS binding protein/regulator Lztfl1. Interestingly, the BBSome and Lztfl1 accumulate to high levels in Ift27 mutant cilia. Because Lztfl1 mutant cells accumulate BBSome but not IFT27, it is likely that Lztfl1 functions downstream of IFT27 to couple the BBSome to the IFT particle for coordinated removal of patched-1 and Smoothened from cilia during hedgehog signaling. Copyright © 2014 Elsevier Inc. All rights reserved.
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              The roles of evolutionarily conserved functional modules in cilia-related trafficking.

              Cilia are present across most eukaryotic phyla and have diverse sensory and motility roles in animal physiology, cell signalling and development. Their biogenesis and maintenance depend on vesicular and intraciliary (intraflagellar) trafficking pathways that share conserved structural and functional modules. The functional units of the interconnected pathways, which include proteins involved in membrane coating as well as small GTPases and their accessory factors, were first experimentally associated with canonical vesicular trafficking. These components are, however, ancient, having been co-opted by the ancestral eukaryote to establish the ciliary organelle, and their study can inform us about ciliary biology in higher organisms.
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                Author and article information

                Contributors
                Role: Investigation
                Role: InvestigationRole: Writing – original draft
                Role: Investigation
                Role: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 March 2018
                2018
                : 13
                : 3
                : e0195005
                Affiliations
                [001]Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
                University of Massachusetts Medical School, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-7701-7183
                Article
                PONE-D-17-42541
                10.1371/journal.pone.0195005
                5874067
                29590217
                f7d47edf-ca43-40a1-9217-0f93895958fa
                © 2018 Nozaki et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 December 2017
                : 14 March 2018
                Page count
                Figures: 6, Tables: 0, Pages: 17
                Funding
                Funded by: the Ministry of Education, Culture, Sports, Science and Technology, Japan
                Award ID: 15H01211
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 15H04370
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 15K07929
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: 16J03865
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100007263, Astellas Foundation for Research on Metabolic Disorders;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008732, Uehara Memorial Foundation;
                Award Recipient :
                This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas “Cilia and Centrosome” from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number 15H01211 to K.N.); grants from the Japan Society for the Promotion of Science (JSPS) (grant numbers 15H04370 to K.N., 15K07929 to Y.K., and 16J03865 to S.N.); and grants from the Astellas Foundation for Research on Metabolic Disorders to K.N., and from the Takeda Science Foundation and the Uehara Memorial Foundation to Y.K. S.N. was supported by a JSPS Research Fellowship.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cilia
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblotting
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblotting
                Biology and Life Sciences
                Biochemistry
                Proteins
                Transmembrane Receptors
                G Protein Coupled Receptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Transmembrane Receptors
                G Protein Coupled Receptors
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Membrane Trafficking
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Hedgehog Signaling
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Protein Transport
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Transport
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Complexes
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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