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Vogel et al. describe a selective exocytic pathway that goes awry in the rare genetic disorder microvillus inclusion disease (MVID).
MVID patients suffer a life-threatening loss of intestinal function shortly after birth. Their intestinal cells lose their apical microvilli, which instead accumulate in intracellular inclusions, while numerous secretory vesicles pile up beneath the apical plasma membrane. Many cases of MVID are caused by mutations in the gene encoding the unconventional myosin motor Myo5B, which is recruited to apical secretory vesicles by the GTPases Rab8 and Rab11.
Vogel et al. found that Myo5B’s interaction with the two Rab proteins promoted its association with other proteins involved in apical transport, including components of the exocyst tethering complex, the vesicle SNARE-like protein Slp4a, and the apical membrane SNARE syntaxin3, whose gene has also been linked to MVID.
The researchers then used genome editing to generate a human intestinal epithelial cell line carrying a MYO5B mutation found in MVID patients. These cells recapitulated the defects seen in patient-derived samples, including the accumulation of vesicles beneath the apical plasma membrane. In these cells, syntaxin3 didn’t associate with its cognate vesicle SNAREs, indicating that Myo5B is required to bring secretory vesicles close enough to the apical membrane for them to undergo SNARE-dependent fusion. Several key proteins, including the sodium/hydrogen exchanger NHE3 and the glucose transporter GLUT5, were not delivered to the apical membrane in MYO5B mutant cells. Several other apical proteins still localized correctly, however, indicating that the Myo5B pathway selectively transports specific apical cargoes. The authors now want to identify ways to restore this pathway when Myo5B’s function is compromised.