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Structuring of the yeast endolysosomal pathway by the Rab5 guanine nucleotide exchange factors Muk1 and Vps9

ABSTRACT: The endolysosomal pathway, with its interconnected endosomes and lysosomes, has key functions in cellular nutrient and ion uptake, metabolic adaptation, as well as protein and organelle turnover via autophagy. Rab5 GTPases are organelle identity markers on endosomes, though it remains unclear why cells have several Rab5 isoforms and guanine nucleotide exchange factors (GEFs) as their activators. Using yeast, we demonstrate that the key Rab5 GEFs Vps9 and Muk1 overlap in their Rab5 specificity in vitro but cover distinct cellular territories in vivo. Vps9 functions between the Golgi and endosomes, while Muk1 is primarily found in the early endocytic pathway. Using targeting approaches, we show that Rab5 GEFs can only partially replace each other, demonstrating that each GEF is specific for its cellular niche. Intriguingly, Muk1 functions in vivo as an oligomer through its C-terminal domain, which is sufficient to also oligomerize a chimeric Vps9. Overall, our data suggest the spatial distribution of Rab5 GEFs and their substrate Rab5s fine-tune the endolysosomal system for cellular needs and metabolic cues.

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ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Bianca Esch

LAB HEAD: Florian Fröhlich

PROVIDER: PXD073596 | Pride | 2026-02-23

REPOSITORIES: Pride

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Project description:Cut-out switch model Membrane identity and GTPase cascades regulated by toggle and cut-out switches Perla Del Conte-Zerial, Lutz Brusch, Jochen C Rink, Claudio Collinet, Yannis Kalaidzidis, Marino Zerial, and Andreas Deutsch: Molecular Systems Biology4:206 15 July 2008, doi:10.1038/msb.2008.45 This is the cut-out switch model for the Rab5 - Rab7 transition, also referred to as model 2 in the original publication. This model is not completely described in all details in the publication. Thanks go to Barbara Szomolay and Lutz Brusch for finding and clarifying this. According to Dr. Brusch this model represents the mechanism identified by the qualitative analysis in the article in the scenario deemed most useful by the authors. For the time-course simulations it was necessary to add a time dependency to one of the parameters, which is only verbally described in the article. As argued in the publication the switch between early and late endosomes can be triggered by a parameter change. While with fixed parameter values each switch just converges to one steady state from its initial conditions and stays there, endosomes should switch between two different states. These changes would in reality of course depend on many different factors, such as cargo composition and amount in the specific endosome, its location and some additional cellular control mechanisms and encompass many different parameters. To keep the model simple the authors chose to add a time dependency to only one reaction - ke in the activation of RAB5 is multiplied with a term monotonously increasing over time from 0 to 1. They also hard coded a time dependence in this term, 100 minutes, to make the switch occur after several hundred minutes. As long as this modulating term remains monotonic all resulting time courses should look similar, with the switching behavior depending on the initial conditions and whether the term is increasing or decreasing. Monotonic increase is a reasonable assumption for the described mechanism of cargo accumulation. Not explicitly described in the article: activation of Rab5 (time) : r*ke*time/(100+time) /(1+e(kg-R)*kf) instead of r*ke/(1+e(kg-R)*kf) This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.

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	mzTab.mzTab	Mztab
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Structuring of the yeast endolysosomal pathway by the Rab5 guanine nucleotide exchange factors Muk1 and Vps9

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