CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking

Szu-Yi Chou, Kuo-Shun Hsu, Wataru Otsu, Ya-Chu Hsu, Yun-Cin Luo, Celine Yeh, Syed S. Shehab, Jie Chen, Vincent Shieh, Guo-an He, Michael B. Marean, Diane Felsen, Aihao Ding, Dix P. Poppas, Jen-Zen Chuang and Ching-Hwa Sung ()
Additional contact information
Szu-Yi Chou: Weill Cornell Medical College
Kuo-Shun Hsu: Weill Cornell Medical College
Wataru Otsu: Weill Cornell Medical College
Ya-Chu Hsu: Weill Cornell Medical College
Yun-Cin Luo: Weill Cornell Medical College
Celine Yeh: Weill Cornell Medical College
Syed S. Shehab: Institute for Pediatric Urology, Weill Cornell Medical College
Jie Chen: Institute for Pediatric Urology, Weill Cornell Medical College
Vincent Shieh: Weill Cornell Medical College
Guo-an He: Weill Cornell Medical College
Michael B. Marean: Institute for Pediatric Urology, Weill Cornell Medical College
Diane Felsen: Institute for Pediatric Urology, Weill Cornell Medical College
Aihao Ding: Weill Cornell Medical College
Dix P. Poppas: Institute for Pediatric Urology, Weill Cornell Medical College
Jen-Zen Chuang: Weill Cornell Medical College
Ching-Hwa Sung: Weill Cornell Medical College

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10412

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