Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, United States
Ke Zoe Shan
Department of Biochemistry, Duke University Medical Center, Durham, United States
Liping Feng
Department of Obstetrics and Gynecology, Duke University Medical Centre, Durham, United States; MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai, China
Yong Chen
Department of Neurology, Duke University Medical Center, Durham, United States
Wolfgang Liedtke
Department of Neurology, Duke University Medical Center, Durham, United States; Department of Anesthesiology, Duke University Medical Center, Durham, United States; Department of Neurobiology, Duke University Medical Center, Durham, United States; College of Dentistry, Department of Molecular Pathobiology, NYU, New York, United States
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, United States; Duke Human Vaccine Institute, Duke University, Durham, United States
Department of Biochemistry, Duke University Medical Center, Durham, United States; Department of Neurobiology, Duke University Medical Center, Durham, United States
TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization, however, how TMEM16F is activated during cell fusion is unclear. Here, using trophoblasts as a model for cell fusion, we demonstrate that Ca2+ influx through the Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and plays a role in subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. We also show that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in a human trophoblast cell line using patch-clamp electrophysiology. Pharmacological inhibition or gene silencing of TRPV4 hinders TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and one of the physiological activation mechanisms of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically and disease-relevant cell fusion events.
