The endocytic pathway taken by cationic substances requires Rab14 but not Rab5 and Rab7

Cell Rep. 2021 Nov 2;37(5):109945. doi: 10.1016/j.celrep.2021.109945.


Endocytosis and endosome dynamics are controlled by proteins of the small GTPase Rab family. Besides possible recycling routes to the plasma membrane and various organelles, previously described endocytic pathways (e.g., clathrin-mediated endocytosis, macropinocytosis, CLIC/GEEC pathway) all appear to funnel the endocytosed material to Rab5-positive early endosomes that then mature into Rab7-positive late endosomes/lysosomes. By studying the uptake of a series of cell-penetrating peptides (CPPs), we identify an endocytic pathway that moves material to nonacidic Lamp1-positive late endosomes. Trafficking via this endocytic route is fully independent of Rab5 and Rab7 but requires the Rab14 protein. The pathway taken by CPPs 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 homeodomains found in homeoproteins.

Keywords: Lamp1; Rab14; Rab5; Rab7; cell-penetrating peptides; endocytosis; endosomes; homeodomains; homeoproteins; polyamines.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cations
  • Cell-Penetrating Peptides / metabolism*
  • Endocytosis*
  • Endosomes / genetics
  • Endosomes / metabolism*
  • HeLa Cells
  • Homeodomain Proteins / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Lysosome-Associated Membrane Glycoproteins / genetics
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Polyamines / metabolism*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism*
  • rab7 GTP-Binding Proteins / genetics
  • rab7 GTP-Binding Proteins / metabolism*


  • Cations
  • Cell-Penetrating Peptides
  • Homeodomain Proteins
  • LAMP1 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Polyamines
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • RAB5C protein, human
  • Rab14 protein, human
  • rab GTP-Binding Proteins
  • rab5 GTP-Binding Proteins