Phosphoinositide (PI) lipids regulate a wide variety of cellular processes, from cell signaling to cytoskeletal dynamics, by controlling the identity and properties of cellular membranes. A large number of PI kinases and phosphatases restrict the distribution of PI species and give each cellular compartment its own, distinct PI signature. When vesicles are transported from one compartment to another, therefore, their PI composition must be modified accordingly. Two papers by Hsu et al. and Nakatsu et al. reveal that the phosphatase Sac2 promotes endocytic trafficking by dephosphorylating PI(4)P (1, 2).

Sac2 is one of five vertebrate proteins that contain a Sac1 phosphatase domain. Other members of the family, including Sac1 itself, have been shown to dephosphorylate PI(4)P, but Sac2 was initially reported to remove the 5ʹ phosphate group from both PI(4,5)P2 and PI(3,4,5)P3 (3). “That puzzled us,”...

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