The Formin INF2 Regulates Basolateral-to-Apical Transcytosis and Lumen Formation in Association with Cdc42 and MAL2

SummaryTranscytosis is a widespread pathway for apical targeting in epithelial cells. MAL2, an essential protein of the machinery for apical transcytosis, functions by shuttling in vesicular carriers between the apical zone and the cell periphery. We have identified INF2, an atypical formin with actin polymerization and depolymerization activities, which is a binding partner of MAL2. MAL2-positive vesicular carriers associate with short actin filaments during transcytosis in a process requiring INF2. INF2 binds Cdc42 in a GTP-loaded-dependent manner. Cdc42 and INF2 regulate MAL2 dynamics and are necessary for apical transcytosis and the formation of lateral lumens in hepatoma HepG2 cells. INF2 and MAL2 are also essential for the formation of the central lumen in organotypic cultures of epithelial MDCK cells. Our results reveal a functional mechanism whereby Cdc42, INF2, and MAL2 are sequentially ordered in a pathway dedicated to the regulation of transcytosis and lumen formation.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (295 K)Download as PowerPoint slideHighlights► Formin INF2 binds to MAL2, a component of the apical transcytosis machinery ► INF2 mediates association of MAL2+ vesicles with actin comets ► Knockdown of INF2 impairs MAL2 distribution and apical transcytosis ► Cdc42 binds to INF2 and is required for apical transcytosis and lumen formation