Human Type IV P-type ATPases That Work as Plasma Membrane Phospholipid Flippases and Their Regulation by Caspase and Calcium

In plasma membranes, flippases translocate aminophospholipids such as phosphatidylserine and phosphatidylethanolamine from the extracellular to the cytoplasmic leaflet. Mammalian ATP11C, a type IV P-type ATPase, acts as a flippase at the plasma membrane. Here, by expressing 12 human type IV P-type ATPases in ATP11C-deficient cells, we determined that ATP8A2 and ATP11A can also act as plasma membrane flippases. As with ATP11C, ATP8A2 and ATP11A localized to the plasma membrane in a CDC50A-dependent manner. ATP11A was cleaved by caspases during apoptosis, and a caspase-resistant ATP11A blocked apoptotic PtdSer exposure. In contrast, ATP8A2 was not cleaved by caspase, and cells expressing ATP8A2 did not expose PtdSer during apoptosis. Similarly, high Ca2+ concentrations inhibited the ATP11A and ATP11C PtdSer flippase activity, but ATP8A2 flippase activity was relatively resistant to Ca2+. ATP11A and ATP11C were ubiquitously expressed in human and mouse adult tissues. In contrast, ATP8A2 was expressed in specific tissues, such as the brain and testis. Thus, ATP8A2 may play a specific role in translocating PtdSer in these tissues.