| First Author | He M | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 52 | Pages | E11161-E11169 |
| PubMed ID | 29229864 | Mgi Jnum | J:255415 |
| Mgi Id | MGI:6107595 | Doi | 10.1073/pnas.1714448115 |
| Citation | He M, et al. (2017) Cytoplasmic Cl(-) couples membrane remodeling to epithelial morphogenesis. Proc Natl Acad Sci U S A 114(52):E11161-E11169 |
| abstractText | Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 approximately 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. |
