An Arf6- And Caveolae-Dependent Pathway Links Hemidesmosome Remodeling And Mechanoresponse

Hemidesmosomes (HDs) are epithelial-specific cell-matrix adhesions, which stably anchor the intracellular keratin network to the extracellular matrix. Although their main role is to protect the epithelial sheet from external mechanical strain, how HDs respond to mechanical stress remains poorly understood. Here we identify a pathway essential for HD remodeling, and outline its role with respect to 6{beta}4 integrin recycling. We find that 6{beta}4 integrin chains localize to the plasma membrane/caveolae and Arf6+ endocytic compartments. Based on FRAP and endocytosis assays, integrin recycling between both sites requires the small GTPase Arf6 and its co-regulators GIT1/{beta}PIX, but neither Caveolin1 (Cav1) nor Cavin1. Strikingly, when keratinocytes are stretched or hypo-osmotically shocked, 6{beta}4 integrin accumulates at cell edges, whereas Cav1 disappears from it. This process, which is isotropic relative to the orientation of stretch, depends on Arf6, Cav1 and Cavin1. We propose that mechanically-induced HD growth involves the isotropic flattening of caveolae (known for their mechanical buffering role) associated with integrin diffusion and turnover.