Inhibition of flippase-like activity by tubulin regulates phosphatidylserine exposure in erythrocytes from hypertensive and diabetic patients

Plasma membrane tubulin is an endogenous regulator of P-ATPases and the unusual accumulation of tubulin in the erythrocyte membrane results in a partial inhibition of some their activities, causing hemorheological disorders like reduced cell deformability and osmotic resistance. These disorders are of particular interest in hypertension and diabetes, where the abnormal increase in membrane tubulin may be related to the disease development. Phosphatidylserine is more exposed on the membrane of diabetic erythrocytes than in healthy cells. In most cells, phosphatidylserine is transported from the exoplasmic to the cytoplasmic leaflet of the membrane by lipid flippases. Here we report that phosphatidylserine is more exposed in erythrocytes from both hypertensive and diabetic patients than in healthy erythrocytes, which could be attributed to the inhibition of flippase activity by tubulin. This is supported by: (i)- the translocation rate of a fluorescent phosphatidylserine analog in hypertensive and diabetic erythrocytes was slower than in healthy cells, (ii)- the pharmacological variation of membrane tubulin in erythrocytes and K562 cells was linked to changes in phosphatidylserine translocation, (iii)- the P-ATPase-dependent phosphatidylserine translocation in inside-out vesicles from human erythrocytes was inhibited by tubulin. These results suggest that tubulin regulates flippase activity and hence the membrane phospholipid asymmetry.