A clathrin-independent pathway is the predominant endocytic mechanism in fibroblasts, say Howes et al., and it boosts cell migration by rapidly internalizing adhesion proteins.
Although clathrin-mediated endocytosis is the best-studied route for internalization, researchers have long known that other pathways also exist. One of these is the clathrin-independent carrier (CLIC) pathway, which also functions without the endocytic coat protein caveolin. CLIC endocytosis seems to specialize in internalizing glycosylphosphatidylinositol-linked membrane proteins, but a lack of definitive markers has hampered efforts to understand the pathway further.
Howes et al. used quantitative electron microscopy to follow the internalization of a non-specific surface marker in fibroblasts. To their surprise, they found that three times as much material was endocytosed through CLICs as through the clathrin-dependent pathway—enough to consume the entire plasma membrane in less than 12 minutes—indicating that the CLIC pathway can rapidly remodel the cell surface. Electron tomography revealed that internalized CLICs have a complex morphology with distinct domains that probably sort cargo to endosomes or back to the plasma membrane.
To find out how fibroblasts use this pathway, Howes et al. purified newly formed CLICs and analyzed their contents by mass spectrometry. The carriers contained many proteins involved in cell migration, which were specifically internalized by CLICs at the leading edge of moving cells. Blocking the pathway impaired fibroblasts' ability to migrate. Senior author Robert Parton now wants to investigate how CLIC endocytosis facilitates cell migration. The pathway may be coordinated with clathrin and caveolin-dependent endocytosis for efficient directional movement.