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

Authors: Christopher Bricogne, Michael Fine, Pedro M. Pereira, Julia Sung, Maha Tijani, Youxue Wang, Ricardo Henriques, Mary K. Collins, Donald W. Hilgemann
Paper published in Scientific Reports, January 2019
Publisher: Nature Publishing Group UK London

TMEM16F is a Ca^2+-gated ion channel that is required for Ca^2+-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 Ca^2+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 Ca^2+, but instead undergo rapid massive endocytosis with PD-1 internalisation. These results establish a new role for TMEM16F as a regulator of Ca^2+activated membrane trafficking.