Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Takatsu, Hiroyuki; Takayama, Masahiro; Naito, Tomoki; Takada, Naoto; Tsumagari, Kazuya; Ishihama, Yasushi; Nakayama, Kazuhisa; Shin, Hye-Won
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 15
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-01338-1
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+ -mediated PKC activation. Importantly, we show that a characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+ -signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase. ATP11C is a flippase that uses ATP hydrolysis to translocate phospholipids at the plasma membrane. Here, the authors show that the activation of Ca2+-dependent protein kinase C increases ATP11C endocytosis thus downregulating phospholipid translocation.