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

Anja Zeigerer, Jerome Gilleron, Roman L. Bogorad, Giovanni Marsico, Hidenori Nonaka, Sarah Seifert, Hila Epstein-Barash, Satya Kuchimanchi, Chang Geng Peng, Vera M. Ruda, Perla Del Conte-Zerial, Jan G. Hengstler, Yannis Kalaidzidis, Victor Koteliansky and Marino Zerial ()
Additional contact information
Anja Zeigerer: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Jerome Gilleron: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Roman L. Bogorad: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Giovanni Marsico: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Hidenori Nonaka: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Sarah Seifert: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Hila Epstein-Barash: Alnylam Pharmaceuticals, Inc.
Satya Kuchimanchi: Alnylam Pharmaceuticals, Inc.
Chang Geng Peng: Alnylam Pharmaceuticals, Inc.
Vera M. Ruda: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School
Perla Del Conte-Zerial: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Jan G. Hengstler: Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany
Yannis Kalaidzidis: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Victor Koteliansky: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Marino Zerial: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany

Nature, 2012, vol. 485, issue 7399, 465-470

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11133

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