title: BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors.
abstract: Cilia harbor sensory receptors for various signaling cascades critical for vertebrate development. However, the mechanisms underlying the ciliary homeostasis of sensory receptors remain elusive. Here, we demonstrate that BBS-4 and BBS-5, two distinct BBSome components, show unexpected functional redundancy in the context of cilia in C. elegans. BBS-4 directly interacts with BBS-5 and the interaction can be disrupted by a conserved mutation identified in human BBS4. Surprisingly, we found that BBS-4 and BBS-5 act redundantly in the BBSome to regulate the ciliary removal, rather than the ciliary entry or retrograde IFT transport, of various sensory receptors. Further analyses indicate that co-depletion of BBS-4 and BBS-5 disrupts the lysosome-targeted degradative sorting of ciliary sensory receptors. Moreover, mammalian BBS4 and BBS5 also interact directly and coordinate the ciliary removal of polycystin 2. Hence, we reveal a novel and highly conserved role for the BBSome in fine-tuning ciliary signaling by regulating the ciliary removal of sensory receptors for lysosomal degradation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Xu
authors.affiliation: 1] Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA [2] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA [2] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1] Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA [2] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Ling
authors.affiliation: 1] Department of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA [2] Mayo Translational PKD Center [3] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000378:metabolism / Q000473:pathology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002923:Cilia / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins; D020125:Mutation, Missense; D028044:Phosphate-Binding Proteins; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C429655:BBS4 protein, human; C487434:BBS5 protein, human; D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D028044:Phosphate-Binding Proteins; D011506:Proteins; D034741:RNA, Small Interfering