An endocytic pathway as a target of tubby for regulation of fat storage
Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chemotaxis; *Endocytosis; Fats; GTPase-Activating Proteins; Models, Biological; Mutation; Signal Transduction; rab GTP-Binding Proteins; rab5 GTP-Binding Proteins
Genetics and Genomics
The tubby loci provide a unique opportunity to study adult-onset obesity. Mutation in either mammalian tubby or its homologue in Caenorhabditis elegans, tub-1, results in increased fat storage. Previously, we have shown that TUB-1 interacts with a new Rab GTPase-activating protein, RBG-3, for the regulation of fat storage. To understand further the molecular mechanism of TUB-1, we identified the Rab GTPase downstream of RBG-3. We found that RBG-3 preferentially stimulates the intrinsic GTPase activity of RAB-7 in both human and C. elegans. Importantly, either mutation or RNA interference knockdown in rab-7 reduces stored fat in wild type and tub-1 mutants. In addition, the small GTPase rab-5 and genes that regulate Rab membrane localization and nucleotide recycling are required for the regulation of fat storage, thereby defining a role for endocytic recycling in this process. We propose that TUB-1 controls receptor or sensory molecule degradation in neurons by regulating a RAB-7-mediated endocytic pathway.
Rights and Permissions
Citation: EMBO Rep. 2007 Oct;8(10):931-8. Epub 2007 Aug 31. Link to article on publisher's site