An endocytic pathway as a target of tubby for regulation of fat storage.
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.
Mukhopadhyay
Arnab
A
Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
Pan
Xiaojing
X
Lambright
David G
DG
Tissenbaum
Heidi A
HA
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D004705:Endocytosis; D005223:Fats / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D029742:Caenorhabditis elegans Proteins; D005223:Fats; D020690:GTPase-Activating Proteins; D000090802:rab7 GTP-Binding Proteins; C504939:tub-1 protein, C elegans; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins