title: The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.
abstract: Bardet-Biedl syndrome (BBS) is a well-known ciliopathy with mutations reported in 18 different genes. Most of the protein products of the BBS genes localize at or near the primary cilium and the centrosome. Near the centrosome, BBS proteins interact with centriolar satellite proteins, and the BBSome (a complex of seven BBS proteins) is believed to play a role in transporting ciliary membrane proteins. However, the precise mechanism by which BBSome ciliary trafficking activity is regulated is not fully understood. Here, we show that a centriolar satellite protein, AZI1 (also known as CEP131), interacts with the BBSome and regulates BBSome ciliary trafficking activity. Furthermore, we show that AZI1 interacts with the BBSome through BBS4. AZI1 is not involved in BBSome assembly, but accumulation of the BBSome in cilia is enhanced upon AZI1 depletion. Under conditions in which the BBSome does not normally enter cilia, such as in BBS3 or BBS5 depleted cells, knock down of AZI1 with siRNA restores BBSome trafficking to cilia. Finally, we show that azi1 knockdown in zebrafish embryos results in typical BBS phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay. These findings associate AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a novel BBS candidate gene.
authors.affiliation: Department of Pediatrics, University of Iowa Interdisciplinary program of genetics, Iowa City, Iowa, United States of America.
authors.forename: Xitiz
authors.initials: X
authors.lastname: Chamling
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Pediatrics, University of Iowa Interdisciplinary program of genetics, Iowa City, Iowa, United States of America ; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Searby
authors.affiliation: Department of Pediatrics, University of Iowa Interdisciplinary program of genetics, Iowa City, Iowa, United States of America.
authors.forename: Gunhee
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Biology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Slusarski
authors.affiliation: Department of Pediatrics, University of Iowa Interdisciplinary program of genetics, Iowa City, Iowa, United States of America ; Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America ; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D002502:Centrioles / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000235:genetics; D003598:Cytoskeletal Proteins; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008868:Microtubule Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000235:genetics; D034741:RNA, Small Interfering; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: C429655:BBS4 protein, human; C000593600:BBS4 protein, zebrafish; C578334:CEP131 protein, human; C000593599:CEP131 protein, zebrafish; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D008868:Microtubule Proteins; D008869:Microtubule-Associated Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins; D020727:ADP-Ribosylation Factors; C548818:ARL6 protein, zebrafish