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Rab5 is necessary for the biogenesis of the endolysosomal system in vivo
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.
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“Similarly, several genes reported to be involved in Aβ catabolism, such as RAB5A, RAB11A, CLU, and LRP2 (49–53), were also down-regulated in AD monocytes, suggesting the impaired Aβ catabolism in AD monocytes.”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [49]
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Metadata
- Authors
- Zeigerer, A., Gilleron, J., Bogorad, R. L., Marsico, G., Nonaka, H., Seifert, S., Epstein-Barash, H., Kuchimanchi, S., Peng, C. G., Ruda, V. M., Conte-Zerial, P. D., Hengstler, J. G., Kalaidzidis, Y., Koteliansky, V., & Zerial, M.
- Affiliations
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Alnylam Pharmaceuticals (United States) (US)
- Harvard University (US)
- Leibniz Research Centre for Working Environment and Human Factors (DE)
- Lomonosov Moscow State University (RU)
- Corresponding author
- Zerial, Marino
- ORCID
- Venue
- Nature
- Published
- 2012-05
- Volume
- 485
- Issue
- 7399
- Pages
- 465-470
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1967182910
- Cited by
- 362
- References
- 51
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 21 · 2023: 17 · 2022: 20 · 2021: 35 · 2020: 22 · 2019: 31 · 2018: 15 · 2017: 30 · 2016: 20 · 2015: 31 · 2014: 47 · 2013: 29 · 2012: 10
- FWCI
- 17.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Site cant be reached (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Rab5, endolysosomal system, small GTPases, endocytosis, early endosomes, late endosomes, lysosomes, hepatocyte polarity, bile canaliculi, mathematical modeling, RNA interference, mouse liver, serum cholesterol
- MeSH terms
- Animals, Cells, Cultured, Endocytosis, Isoenzymes, Lipoproteins, LDL, Liver, Lysosomes, Organ Specificity, Endosomes, RNA, Messenger, Time Factors, Protein Biosynthesis, Cell Polarity, rab5 GTP-Binding Proteins, Hepatocytes, Vesicular Transport Proteins, RNA Interference, Mice, Gene Knockdown Techniques, Multivesicular Bodies
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