Evgeniya Trofimenko, Yuta Homma, Mitsunori Fukuda, Christian Widmann
Endocytosis and endosome dynamics are controlled by proteins of the small GTPase Rab family. Besidespossible recycling routes to the plasma membrane and various organelles, previously described endocyticpathways (e.g., clathrin-mediated endocytosis, macropinocytosis, CLIC/GEEC pathway) all appear to funnelthe endocytosed material to Rab5-positive early endosomes that then mature into Rab7-positive late endo-somes/lysosomes. By studying the uptake of a series of cell-penetrating peptides (CPPs), we identify anendocytic pathway that moves material to nonacidic Lamp1-positive late endosomes. Trafficking via this en-docytic route is fully independent of Rab5 and Rab7 but requires the Rab14 protein. The pathway taken byCPPs differs from the conventional Rab5-dependent endocytosis at the stage of vesicle formation already,as it is not affected by a series of compounds that inhibit macropinocytosis or clathrin-mediated endocytosis.The Rab14-dependent pathway is also used by physiological cationic molecules such as polyamines and ho-meodomains found in homeoproteins.