Abstract

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.

Links

Publisher Full Text

Publisher Full Text

Authors

Zeigerer A, Gilleron J, Bogorad RL, Marsico G, Nonaka H, Seifert S, Epstein-Barash H, Kuchimanchi S, Peng CG, Ruda VM, Del Conte-Zerial P, Hengstler JG, Kalaidzidis Y, Koteliansky V, Zerial M

Institution

Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

Source

Nature 485:7399 2012 May 24 pg 465-70

MeSH

Animals
Cell Polarity
Cells, Cultured
Endocytosis
Endosomes
Gene Knockdown Techniques
Hepatocytes
Isoenzymes
Lipoproteins, LDL
Liver
Lysosomes
Mice
Multivesicular Bodies
Organ Specificity
Protein Biosynthesis
RNA Interference
RNA, Messenger
Time Factors
Vesicular Transport Proteins
rab5 GTP-Binding Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22622570