title: CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking.
abstract: Chloride intracellular channel 4 (CLIC4) is a mammalian homologue of EXC-4 whose mutation is associated with cystic excretory canals in nematodes. Here we show that CLIC4-null mouse embryos exhibit impaired renal tubulogenesis. In both developing and developed kidneys, CLIC4 is specifically enriched in the proximal tubule epithelial cells, in which CLIC4 is important for luminal delivery, microvillus morphogenesis, and endolysosomal biogenesis. Adult CLIC4-null proximal tubules display aberrant dilation. In MDCK 3D cultures, CLIC4 is expressed on early endosome, recycling endosome and apical transport carriers before reaching its steady-state apical membrane localization in mature lumen. CLIC4 suppression causes impaired apical vesicle coalescence and central lumen formation, a phenotype that can be rescued by Rab8 and Cdc42. Furthermore, we show that retromer- and branched actin-mediated trafficking on early endosome regulates apical delivery during early luminogenesis. CLIC4 selectively modulates retromer-mediated apical transport by negatively regulating the formation of branched actin on early endosomes.
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Kuo-Shun
authors.initials: KS
authors.lastname: Hsu
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Otsu
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Yun-Cin
authors.initials: YC
authors.lastname: Luo
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Yeh
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Syed S
authors.initials: SS
authors.lastname: Shehab
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Shieh
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Guo-an
authors.initials: GA
authors.lastname: He
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Marean
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Felsen
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Aihao
authors.initials: A
authors.lastname: Ding
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Dix P
authors.initials: DP
authors.lastname: Poppas
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Jen-Zen
authors.initials: JZ
authors.lastname: Chuang
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.|Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Sung
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics / Q000502:physiology; D047468:Immunoprecipitation; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology
chemical_list: D000199:Actins; C479423:CLIC protein, mouse; D018118:Chloride Channels; D024101:Mitochondrial Proteins