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Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Significance In healthy cells, phosphatidylserine (PtdSer) is exclusively localized at inner leaflets of plasma membranes. When cells undergo apoptosis, caspases cleave a membrane protein, XK-related protein (Xkr) 8, at the C terminus, and the cleaved Xkr8 supports scrambling of phospholipids between inner and outer leaflets of plasma membranes. The PtdSer, thus exposed to the cell surface, is recognized by macrophages as an “eat me” signal for engulfment of dead cells. We report that Xkr8 is present as a complex with basigin or neuroplastin that work as a chaperone to localize Xkr8 at plasma membranes. When Xkr8 is cleaved by caspase, the complex undergoes a higher-order structure. These results will contribute to our understanding of how the Xkr8 scrambles phospholipids when cells undergo apoptosis. Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG−/−NPTN−/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG’s association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.