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Sci Rep. 2019 Jan 24;9(1):619. doi: 10.1038/s41598-018-37056-x.

TMEM16F activation by Ca2+ triggers plasma membrane expansion and directs PD-1 trafficking.

Author information

1
UCL Cancer Institute, University College London, Gower St, London, UK.
2
University of Texas Southwestern Medical Center, Department of Physiology, Dallas, Texas, USA.
3
MRC Laboratory for Molecular Cell Biology, University College London, Gower St, London, UK.
4
National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Herts, UK.
5
UCL Cancer Institute, University College London, Gower St, London, UK. mary.collins@oist.jp.
6
National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Herts, UK. mary.collins@oist.jp.
7
Okinawa Institute of Science and Technology, Onna-son, Okinawa, Japan. mary.collins@oist.jp.
8
University of Texas Southwestern Medical Center, Department of Physiology, Dallas, Texas, USA. donald.hilgemann@utsouthwestern.edu.

Abstract

TMEM16F is a Ca2+ -gated ion channel that is required for Ca2+ -activated phosphatidylserine exposure on the surface of many eukaryotic cells. TMEM16F is widely expressed and has roles in platelet activation during blood clotting, bone formation and T cell activation. By combining microscopy and patch clamp recording we demonstrate that activation of TMEM16F by Ca2+ ionophores in Jurkat T cells triggers large-scale surface membrane expansion in parallel with phospholipid scrambling. With continued ionophore application,TMEM16F-expressing cells then undergo extensive shedding of ectosomes. The T cell co-receptor PD-1 is selectively incorporated into ectosomes. This selectivity depends on its transmembrane sequence. Surprisingly, cells lacking TMEM16F not only fail to expand surface membrane in response to elevated cytoplasmic Ca2+, but instead undergo rapid massive endocytosis with PD-1 internalisation. These results establish a new role for TMEM16F as a regulator of Ca2+ activated membrane trafficking.

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