Rab5 is necessary for the biogenesis of the endolysosomal system in vivo

Nature. 2012 May 23;485(7399):465-70. doi: 10.1038/nature11133.


An outstanding question is how cells control the number and size of membrane organelles. The small GTPase Rab5 has been proposed to be a master regulator of endosome biogenesis. Here, to test this hypothesis, we developed a mathematical model of endosome dependency on Rab5 and validated it by titrating down all three Rab5 isoforms in adult mouse liver using state-of-the-art RNA interference technology. Unexpectedly, the endocytic system was resilient to depletion of Rab5 and collapsed only when Rab5 decreased to a critical level. Loss of Rab5 below this threshold caused a marked reduction in the number of early endosomes, late endosomes and lysosomes, associated with a block of low-density lipoprotein endocytosis. Loss of endosomes caused failure to deliver apical proteins to the bile canaliculi, suggesting a requirement for polarized cargo sorting. Our results demonstrate for the first time, to our knowledge, the role of Rab5 as an endosome organizer in vivo and reveal the resilience mechanisms of the endocytic system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity
  • Cells, Cultured
  • Endocytosis
  • Endosomes / metabolism*
  • Gene Knockdown Techniques
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Isoenzymes / biosynthesis
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lipoproteins, LDL / metabolism
  • Liver / cytology
  • Liver / enzymology
  • Liver / metabolism
  • Lysosomes / metabolism*
  • Mice
  • Multivesicular Bodies / metabolism
  • Organ Specificity
  • Protein Biosynthesis
  • RNA Interference
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Time Factors
  • Vesicular Transport Proteins / metabolism
  • rab5 GTP-Binding Proteins / biosynthesis
  • rab5 GTP-Binding Proteins / deficiency
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism*


  • Isoenzymes
  • Lipoproteins, LDL
  • RNA, Messenger
  • Vesicular Transport Proteins
  • early endosome antigen 1
  • rab5 GTP-Binding Proteins