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

Author

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  • 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
    Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119899, Moscow, Russia)

  • Victor Koteliansky

    (Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
    Alnylam Pharmaceuticals, Inc.)

  • Marino Zerial

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

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.

Suggested Citation

  • 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-Zer, 2012. "Rab5 is necessary for the biogenesis of the endolysosomal system in vivo," Nature, Nature, vol. 485(7399), pages 465-470, May.
    • Handle: RePEc:nat:nature:v:485:y:2012:i:7399:d:10.1038_nature11133
    DOI: 10.1038/nature11133
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    Cited by:

    1. Sergei Fedotov & Dmitri Alexandrov & Ilya Starodumov & Nickolay Korabel, 2022. "Stochastic Model of Virus–Endosome Fusion and Endosomal Escape of pH-Responsive Nanoparticles," Mathematics, MDPI, vol. 10(3), pages 1-11, January.

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