RabGEFs are a major determinant for specific Rab membrane targeting

• Published in: The Journal of cell biology Vol. 200; no. 3; pp. 287 - 300
• Main Authors: Blümer, Julia, Rey, Juliana, Dehmelt, Leif, Mazel, Tomáš, Wu, Yao-Wen, Bastiaens, Philippe, Goody, Roger S, Itzen, Aymelt
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.02.2013; The Rockefeller University Press
• Subjects: Adenosine triphosphatase; Animals; Cell Membrane - metabolism; Cellular biology; Cercopithecus aethiops; COS Cells; Eukaryotes; Guanine Nucleotide Exchange Factors - chemistry; Guanine Nucleotide Exchange Factors - metabolism; Humans; Membranes; Microscopy, Confocal; Mitochondria - metabolism; Mitochondrial Membranes - metabolism; Models, Biological; Mutant Proteins - metabolism; Protein Structure, Tertiary; Protein Transport; Proteins; rab GTP-Binding Proteins - chemistry; rab GTP-Binding Proteins - metabolism; rab5 GTP-Binding Proteins - metabolism; Subcellular Fractions - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201209113

Eukaryotic cells critically depend on the correct regulation of intracellular vesicular trafficking to transport biological material. The Rab subfamily of small guanosine triphosphatases controls these processes by acting as a molecular on/off switch. To fulfill their function, active Rab proteins need to localize to intracellular membranes via posttranslationally attached geranylgeranyl lipids. Each member of the manifold Rab family localizes specifically to a distinct membrane, but it is unclear how this specific membrane recruitment is achieved. Here, we demonstrate that Rab-activating guanosine diphosphate/guanosine triphosphate exchange factors (GEFs) display the minimal targeting machinery for recruiting Rabs from the cytosol to the correct membrane using the Rab-GEF pairs Rab5A-Rabex-5, Rab1A-DrrA, and Rab8-Rabin8 as model systems. Specific mistargeting of Rabex-5/DrrA/Rabin8 to mitochondria led to catalytic recruitment of Rab5A/Rab1A/Rab8A in a time-dependent manner that required the catalytic activity of the GEF. Therefore, RabGEFs are major determinants for specific Rab membrane targeting.