Cytoplasmic Cl⁻ couples membrane remodeling to epithelial morphogenesis

Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 ∼ 20 mM). Cytoplasmic Cl⁻ level is dynamically regulated by Cl⁻ channels and transporters. It is well established that movement of Cl⁻ across the cell membrane is coupled with cell exc...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 52; pp. E11161 - E11169
Main Authors:	He, Mu, Ye, Wenlei, Wang, Won-Jing, Sison, Eirish S., Jan, Yuh Nung, Jan, Lily Yeh
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-12-2017
Series:	PNAS Plus
Subjects:	Adherens Junctions - genetics Adherens Junctions - metabolism Animals Anoctamin-1 - genetics Anoctamin-1 - metabolism Biological Sciences Calcium Calcium chloride Cell Membrane - genetics Cell Membrane - metabolism Chloride channels (calcium-gated) Chlorides - metabolism Cilia - genetics Cilia - metabolism Cytoplasm Epithelium - metabolism Eukaryotes Excitability Genetics Homeostasis Intracellular signalling Ion Transport - physiology Membrane potential Membrane proteins Membrane trafficking Membranes Mice Morphogenesis Morphogenesis - physiology Pharmacology Phosphatidylinositol 4,5-diphosphate Phosphatidylinositol 4,5-Diphosphate - genetics Phosphatidylinositol 4,5-Diphosphate - metabolism PNAS Plus Proteins Secretion Tissues membrane remodeling epithelial morphogenesis calcium-activated chloride channel primary cilia phosphoinositide
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Summary:	Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 ∼ 20 mM). Cytoplasmic Cl⁻ level is dynamically regulated by Cl⁻ channels and transporters. It is well established that movement of Cl⁻ across the cell membrane is coupled with cell excitability through changes in membrane potential and with water secretion. However, whether cytoplasmic Cl⁻ plays additional roles in animal development and tissue homeostasis is unknown. Here we use genetics, cell biological and pharmacological tools to demonstrate that TMEM16A, an evolutionarily conserved calcium-activated chloride channel (CaCC), regulates cytoplasmic Cl⁻ homeostasis and promotes plasma membrane remodeling required for mammalian epithelial morphogenesis. We demonstrate that TMEM16A-mediated control of cytoplasmic Cl⁻ regulates the organization of the major phosphoinositide species PtdIns(4,5)P₂ into microdomains on the plasma membrane, analogous to processes that cluster soluble and membrane proteins into phase-separated droplets. We further show that an adequate cytoplasmic Cl⁻ level is required for proper endocytic trafficking and membrane supply during early stages of ciliogenesis and adherens junction remodeling. Our study thus uncovers a critical function of CaCC-mediated cytoplasmic Cl⁻ homeostasis in controlling the organization of PtdIns(4,5)P₂ microdomains and membrane remodeling. This newly defined role of cytoplasmic Cl⁻ may shed light on the mechanisms of intracellular Cl⁻ signaling events crucial for regulating tissue architecture and organelle biogenesis during animal development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed by Lily Yeh Jan, November 18, 2017 (sent for review August 16, 2017; reviewed by Bingwei Lu and Blanche Schwappach) Author contributions: M.H., Y.N.J., and L.Y.J. designed research; M.H., W.Y., W.-J.W., and E.S.S. performed research; M.H., W.Y., and W.-J.W. analyzed data; and M.H., Y.N.J., and L.Y.J. wrote the paper. Reviewers: B.L., Stanford University School of Medicine; and B.S., Institute of Molecular Biology, Universitätsmedizin Göttingen.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1714448115