FBXO16 (F-box only protein 16) is an F-box "other" (FBXO) family protein that serves as the substrate-recognition component of an SCF (SKP1-CUL1-F-box protein) / CRL1 Cullin-RING E3 ubiquitin-protein ligase complex. Through its F-box domain (residues 86-132) it docks onto SKP1 within the SCF scaffold, while its C-terminal region recruits specific substrate proteins for ubiquitination and subsequent proteasomal degradation; the catalytic transfer of ubiquitin is performed by the RING subunit RBX1 and an E2 enzyme, not by FBXO16 itself; consistently, its F-box domain is required for assembling a functional ligase complex while its C-terminal region mediates substrate recognition (e.g. binding the RRM3 domain of hnRNPL and the C-terminus being essential for beta-catenin binding). FBXO16 acts predominantly in the nucleus and drives K48-linked polyubiquitination of its targets. Reported substrates include the nuclear pool of beta-catenin/CTNNB1 (suppressing Wnt/TCF output such as c-Myc and Cyclin D1), the RNA-binding protein hnRNPL (whose degradation restrains MAPK/RAS/Wnt outputs), the autophagy-initiating kinase ULK1 (K48-linked polyubiquitination, suppressing autophagy), and the NF-kappa-B subunit RELA/p65 (as the substrate-recognition component of a PDLIM2-containing CRL1 complex that degrades nuclear p65). Through these targets FBXO16 has been implicated as a putative tumor suppressor (attenuating beta-catenin-driven epithelial-to-mesenchymal transition and ovarian/glioblastoma progression; in ovarian cancer it is down-regulated by MIR937 amplification, stabilizing ULK1) and as a negative regulator of NF-kappa-B inflammatory signaling. The protein is expressed in several tissues (heart, spleen, colon; tissue-enhanced in epididymis and pituitary) and exists as two alternatively spliced isoforms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome (Y2H) interactions of FBXO16 captured by IntAct, including LMO1, MORF4L1/MORF4L2, NXT1 and TRIM54. These are real interactions but the bare protein binding term is uninformative about molecular function. Reason: Documents genuine physical interactions recorded by IntAct, but per curation guidelines bare protein binding is uninformative and not a core molecular function. The functionally meaningful substrate interactions (CTNNB1, HNRNPL, RELA, ULK1) come from dedicated studies, not this high-throughput screen. Supporting Evidence: file:human/FBXO16/FBXO16-uniprot.txt Q8IX29; P25800: LMO1; NbExp=3; IntAct=EBI-12063229, EBI-8639312; file:human/FBXO16/FBXO16-uniprot.txt Q8IX29; Q9UKK6: NXT1; NbExp=5; IntAct=EBI-12063229, EBI-301889; |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: FBXO16 is the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, as recorded by ComplexPortal (CPX-7926, "SCF E3 ubiquitin ligase complex, FBXO16 variant"). This is the core localization/complex membership of the protein. Reason: Core complex membership. FBXO16 contains a bona fide F-box domain (residues 86-132) and is annotated by ComplexPortal as the variable F-box subunit of an SCF complex; UniProt explicitly states it is part of an SCF ligase complex. Supporting Evidence: file:human/FBXO16/FBXO16-uniprot.txt Substrate recognition component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. file:human/FBXO16/FBXO16-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: As the substrate receptor of an SCF complex, FBXO16 directs target proteins (e.g. nuclear beta-catenin, hnRNPL, RELA, ULK1) into SCF-dependent proteasomal degradation. This captures the core biological process FBXO16 participates in. Reason: Core biological process. UniProt FUNCTION documents that FBXO16 mediates ubiquitination and subsequent proteasomal degradation of multiple substrates as the substrate-recognition component of an SCF complex, consistent with this SCF-dependent catabolic process term. Falcon-sourced primary literature grounds this with multiple validated K48-linked substrates (nuclear beta-catenin, hnRNPL, ULK1, nuclear p65/RELA), matching the functional placement of FBXO16 as an F-box/SCF (CRL1) substrate-recognition receptor. Supporting Evidence: file:human/FBXO16/FBXO16-uniprot.txt Substrate recognition component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. file:human/FBXO16/FBXO16-deep-research-falcon.md FBXO16 physically interacts with Ξ²-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of Ξ²-catenin, suppressing Wnt/TCF transcriptional output. |
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Download this section (compressed HTML)Q: Which E2 conjugating enzyme and ubiquitin-chain topology does the FBXO16-containing SCF complex use across its different substrates, and is the K48-linked chain reported for ULK1 a general feature of FBXO16-mediated degradation?
Q: How is FBXO16 substrate selection regulated (e.g. by substrate phosphodegron, FBXO16 expression/MIR937 amplification, accessory partners such as PDLIM2, or subcellular localization such as the nuclear beta-catenin/p65 pools), and which substrate relationship is physiologically dominant in a given tissue?
Q: Is FBXO16 a predominantly nuclear CRL1 substrate receptor as the functional studies suggest, and does its nuclear localization explain its preference for nuclear substrate pools (nuclear beta-catenin, hnRNPL, nuclear p65)?
Experiment: Reconstitute the FBXO16-SKP1-CUL1-RBX1 SCF complex in vitro with a defined E2 panel and a candidate substrate (e.g. recombinant ULK1, CTNNB1, or hnRNPL) to confirm that FBXO16 functions as a substrate adaptor, map the C-terminal substrate-binding region, and determine the ubiquitin-chain linkage produced on each substrate.
Experiment: Perform quantitative ubiquitinome/proteome profiling in FBXO16-knockout versus wild-type cells (and with F-box-domain deletion mutants that cannot bind SKP1) to define the endogenous substrate repertoire and confirm that substrate stabilization requires intact SCF assembly.
Experiment: Determine FBXO16 subcellular localization (fractionation, immunofluorescence, tagged endogenous knock-in) and test whether nuclear targeting is required for degradation of nuclear substrates such as beta-catenin and p65, including the contribution of the PDLIM2-containing CRL1 complex.
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