TMEM55A-mediated PI5P signaling regulates α-cell actin depolymerization and glucagon secretion.

Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet α-cells, although the underlying mechanisms regulating glucagon secretion and α-cell dysfunction remain unclear. While insulin secretion from pancreatic β-cells has long been known to be partly controlled by intracellular phospholipid signaling, very little is known about the role of phospholipids in glucagon secretion. Here we show that TMEM55A, a lipid phosphatase that dephosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-5-phosphate (PI5P), regulates α-cell exocytosis and glucagon secretion. TMEM55A knockdown in both human and mouse α-cells reduces exocytosis at low glucose, and this is rescued by the direct reintroduction of PI5P. This does not occur through an effect on Ca channel activity, but through a re-modelling of cortical F-actin dependent upon TMEM55A lipid phosphatase activity which occurs in response to oxidative stress. In summary, we reveal a novel pathway by which TMEM55A regulates α-cell exocytosis by manipulating intracellular PI5P level and the F-actin network.