Figure 2.

Loss of MYO5B induces apical bulk endocytosis and deficits in apical transporter trafficking: a target for therapeutic intervention. (A) Molecular mechanism of microvillus inclusion formation through apical bulk endocytosis induced by MYO5B loss. (Upper panels) F-actin (phalloidin, green) staining shows uniform brush borders in healthy control mouse intestine. Microvillus inclusions form from invaginations of the apical membranes of enterocytes through a process of apical bulk endocytosis in the MYO5B KO mouse (white arrows). Microvillus inclusions that are attached to the apical membrane demonstrate the process of apical bulk endocytosis. Lower diagram shows the topologies of intracellular proteins that are involved in apical bulk endocytosis and microvillus inclusion formation (adapted from Engevik et al⁷⁷). (B) LPA treatment ameliorates brush border structure and SGLT1 localization in vivo and in mouse enteroids. Immunostaining for SGLT1 (magenta), ACTG1 (green), and LAMP1 (yellow) indicate localization of the Na-glucose co-transporter, cell membrane and brush borders, and lysosomes, respectively. Mature brush borders containing SGLT1 are shown in white in control tissues. Tamoxifen-induced MYO5B KO mice with vehicle treatment show expanded lysosomes and disrupted brush border. Both mouse tissues and enteroids treated with LPA partly recover brush border structure and SGLT1 localization on the apical membrane (adapted from Kaji et al⁸⁴). It is notable that LPA treatment does not alter inclusion formation, suggesting that apical bulk endocytosis and trafficking defects are separable.