Mature secretory vesicles (arrows) are missing in the absence of the phosphatase MEG2.

Cellular constipation can be deadly, according to a study on page 1587. Wang and colleagues show that cells get clogged with aborted secretory cargo when they lack an enzyme that helps form vesicles. Deletion of this enzyme proved lethal in mice, halting brain, bone and vascular development.

The enzyme in question is a protein tyrosine phosphatase (PTP) called MEG2. MEG2 binds lipids and resides on intracellular vesicle membranes, where it clips phosphate residues from the fusion protein NSF. Once dephosphorylated, NSF initiates homotypic fusion between immature secretory vesicles, a critical step in protein secretion.

Knocking out MEG2, the team found, prevented T cells (isolated from chimeric mice) from secreting the autocrine growth factor interleukin-2, stunting T cell proliferation in response to stimulation. Electron micrographs of the deficient T cells revealed that the cells lacked mature secretory vesicles and were clogged with the dense remains of fusion-incompetent vesicles.

Platelets that lacked MEG2 were also dysfunctional, failing to aggregate when exposed to the clotting factor thrombin. But the MEG2 defect spared neutrophils and macrophages, although these cells rely on the same cellular machinery for vesicle release.

Cell type–specific PTPs might compensate for MEG2's absence in neutrophils and macrophages. Besides looking for these PTPs, the group is also investigating the mechanism behind the developmental defects in the MEG2-deficient mice, which they suspect result from an inability to produce growth factors that direct the migration and differentiation of progenitor cells.