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An endocytic pathway as a target of tubby for regulation of fat storage.

ABSTRACT: 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.

SUBMITTER: Mukhopadhyay A

PROVIDER: S-EPMC2002550 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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An endocytic pathway as a target of tubby for regulation of fat storage.

Mukhopadhyay Arnab A Pan Xiaojing X Lambright David G DG Tissenbaum Heidi A HA

EMBO reports 20070831 10

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 ac ...[more]

PMID: 17762880

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Project description:BackgroundThe regulatory mechanism underlying the interaction of the Rabex-5 MIU domain with ubiquitinated cargos remains unclear.ResultsRabex-5 guanine nucleotide exchange factor (GEF) mutants affected interactions of ubiquitinated cargos.ConclusionGDP/GTP exchange in the GEF domain controls the MIU domain interactions with the ubiquitinated cargos.SignificanceRabex-5 GEF activity acts as an intramolecular switch for spatiotemporal trafficking of the ubiquitinated cargos. Ubiquitin (Ub)-dependent endocytosis of membrane proteins requires precise molecular recognition of ubiquitinated cargo by Ub-binding proteins (UBPs). Many UBPs are often themselves monoubiquitinated, a mechanism referred to as coupled monoubiquitination, which prevents them from binding in trans to the ubiquitinated cargo. However, the spatiotemporal regulatory mechanism underlying the interaction of UBPs with the ubiquitinated cargo, via their Ub-binding domains (UBDs) remains unclear. Previously, we reported the interaction of Rabex-5, a UBP and guanine nucleotide exchange factor (GEF) for Rab5, with ubiquitinated neural cell adhesion molecule L1, via its motif interacting with Ub (MIU) domain. This interaction is critical for the internalization and sorting of the ubiquitinated L1 into endosomal/lysosomal compartments. The present study demonstrated that the interaction of Rabex-5 with Rab5 depends specifically on interaction of the MIU domain with the ubiquitinated L1 to drive its internalization. Notably, impaired GEF mutants and the Rabex-5(E213A) mutant increased the flexibility of the hinge region in the HB-VPS9 tandem domain, which significantly affected their interactions with the ubiquitinated L1. In addition, GEF mutants increased the catalytic efficiency, which resulted in a reduced interaction with the ubiquitinated L1. Furthermore, the coupled monoubiquitination status of Rabex-5 was found to be significantly associated with interaction of Rabex-5 and the ubiquitinated L1. Collectively, our study reveals a novel mechanism, wherein the GEF activity of Rabex-5 acts as an intramolecular switch orchestrating ubiquitinated cargo-binding activity and coupled monoubiquitination to permit the spatiotemporal dynamic exchange of the ubiquitinated cargos.

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An endocytic pathway as a target of tubby for regulation of fat storage.

Publications

An endocytic pathway as a target of tubby for regulation of fat storage.

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