Uaf1 (WD repeat-containing protein 48 homolog) is the fly ortholog of USP1-associated factor 1, a WD40 beta-propeller protein that binds and allosterically activates ubiquitin-specific proteases of the USP1/USP12/USP46 family. In Drosophila it is a regulatory subunit, with Wdr20, of the Usp12-46 deubiquitylase complex: it stabilizes Usp12-46 and increases its catalytic turnover. The complex deubiquitylates the Wingless co-receptor Arrow/LRP6, raising its cell-surface level and the sensitivity of cells to Wingless, so Uaf1 promotes Wingless signaling strength. By analogy with human UAF1, it may also partner USP1 in DNA damage tolerance and homologous recombination. Uaf1 is predicted to be nuclear.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000724 double-strand break repair via homologous recombination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Double-strand break repair via HR (IBA). Reason: IBA from PTN000458477 (donor MGI:1914811 Wdr48). Mammalian UAF1 acts with USP1 in Fanconi anemia/HR repair; plausible for fly Uaf1 but untested and peripheral to its characterized Usp46-complex role. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nucleus (ISS from human UAF1). Reason: Human UAF1 is nuclear and cytoplasmic; acceptable by similarity. |
| GO:0035800 deubiquitinase activator activity | TAS PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Deubiquitinase activator activity. Reason: Uaf1, like Wdr20, potentiates Usp12/46 catalytic efficiency allosterically and stabilizes Usp46; its own molecular function within the complex. Supporting Evidence: PMID:37798281 WDR20 and UAF1 potentiate the activity of USP12 and USP46 by allosterically increasing their catalytic efficiency without increasing their substrate-binding affinity PMID:37798281 Wdr20, and to a lesser extent Uaf1, stabilized Usp46, as knockdown of either Uaf1 or Wdr20 reduced Usp46 levels |
| GO:0043130 ubiquitin binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ubiquitin binding (IBA/ISS from yeast). Reason: Transferred from yeast WD40 proteins (SGD donors); no fly or mammalian evidence that UAF1 binds ubiquitin itself as part of its function (it binds the USP and substrates). Peripheral; retained pending evidence. |
| GO:0043130 ubiquitin binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ubiquitin binding (IBA/ISS from yeast). Reason: Transferred from yeast WD40 proteins (SGD donors); no fly or mammalian evidence that UAF1 binds ubiquitin itself as part of its function (it binds the USP and substrates). Peripheral; retained pending evidence. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IMP PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Positive regulation of canonical Wnt signaling. Reason: The Usp46-Uaf1-Wdr20 complex deubiquitylates and stabilizes the Wingless co-receptor Arrow, increasing Wg signaling strength; Uaf1 depletion reduces Wg target expression. Defining physiological role of the complex. Supporting Evidence: PMID:37798281 RNAi-mediated depletion of Wdr20 and Uaf1 had comparable effects PMID:37798281 Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/Ξ²-catenin, and attenuates or abolishes Wingless target gene activation |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | NAS PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Positive regulation of canonical Wnt signaling. Reason: The Usp46-Uaf1-Wdr20 complex deubiquitylates and stabilizes the Wingless co-receptor Arrow, increasing Wg signaling strength; Uaf1 depletion reduces Wg target expression. Defining physiological role of the complex. Supporting Evidence: PMID:37798281 RNAi-mediated depletion of Wdr20 and Uaf1 had comparable effects PMID:37798281 Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/Ξ²-catenin, and attenuates or abolishes Wingless target gene activation |
| GO:1905368 peptidase complex | IPI PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Peptidase complex (Usp46-Uaf1-Wdr20). Reason: Uaf1 is a subunit of the Usp12-46 deubiquitylase complex; GO has no more specific term for the USP12/46-UAF1-WDR20 complex, so this is as precise as available. Supporting Evidence: PMID:37798281 We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. |
| GO:1905368 peptidase complex | NAS PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Peptidase complex (Usp46-Uaf1-Wdr20). Reason: Uaf1 is a subunit of the Usp12-46 deubiquitylase complex; GO has no more specific term for the USP12/46-UAF1-WDR20 complex, so this is as precise as available. Supporting Evidence: PMID:37798281 We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. |
| GO:2000059 negative regulation of ubiquitin-dependent protein catabolic process | IDA PMID:37798281 The USP46 deubiquitylase complex increases Wingless/Wnt sign... | ACCEPT | Summary: Negative regulation of ubiquitin-dependent protein catabolic process. Reason: The complex reduces Arrow ubiquitylation and turnover (Arrow is degraded in lysosomes); Uaf1 contributes to this stabilization. Core process. Supporting Evidence: PMID:37798281 By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow |
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Download this section (compressed HTML)Q: Does fly Uaf1 also partner Usp1 in DNA damage tolerance, as in mammals?
Q: Should GO add a specific USP12/USP46-UAF1-WDR20 deubiquitinase complex term in place of the generic peptidase complex?
Experiment: Test Uaf1 and Usp1 mutants or RNAi for sensitivity to DNA crosslinkers and PCNA/FANCD2 monoubiquitination levels.
Hypothesis: Fly Uaf1 acts with Usp1 in DNA damage responses independently of Usp12-46.
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