title: 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.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Zeigerer
authors.forename: Jerome
authors.initials: J
authors.lastname: Gilleron
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsico
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nonaka
authors.forename: Sarah
authors.initials: S
authors.lastname: Seifert
authors.forename: Hila
authors.initials: H
authors.lastname: Epstein-Barash
authors.forename: Satya
authors.initials: S
authors.lastname: Kuchimanchi
authors.forename: Chang Geng
authors.initials: CG
authors.lastname: Peng
authors.forename: Vera M
authors.initials: VM
authors.lastname: Ruda
authors.forename: Perla
authors.initials: P
authors.lastname: Del Conte-Zerial
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Yannis
authors.initials: Y
authors.lastname: Kalaidzidis
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Marino
authors.initials: M
authors.lastname: Zerial
mesh_terms: D000818:Animals; D016764:Cell Polarity; D002478:Cells, Cultured; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D057146:Multivesicular Bodies / Q000378:metabolism; D009928:Organ Specificity; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013997:Time Factors; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D020696:rab5 GTP-Binding Proteins