FBXO16

UniProt ID: Q8IX29
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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 β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output.

Core Functions

Substrate-recognition (F-box) component of an SCF/CRL1 E3 ubiquitin ligase complex that binds specific substrate proteins (e.g. nuclear beta-catenin/CTNNB1, hnRNPL, RELA/p65, ULK1) and presents them, via SKP1 and the CUL1-RBX1 catalytic core, for polyubiquitination and proteasomal degradation. Acts as a ubiquitin-ligase substrate adaptor rather than the catalytic ligase.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
In Complex:
SCF ubiquitin 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.

References

PMID:32296183
A reference map of the human binary protein interactome.
  • High-throughput yeast two-hybrid binary interactome map that records FBXO16 interactions (e.g. LMO1, MORF4L1, MORF4L2, NXT1, TRIM54) deposited in IntAct.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  • Review of SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes and their role in genome/chromosome stability; cited by ComplexPortal as supporting reference for SCF complex membership and SCF-dependent proteasomal degradation.
file:human/FBXO16/FBXO16-deep-research-falcon.md
Falcon deep research report for human FBXO16
  • FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.
    "**FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.**"
  • The FBXO16 F-box domain is required for ligase complex formation while its C-terminal region mediates substrate recognition (e.g. binding the hnRNPL RRM3 domain; C-terminus essential for beta-catenin binding).
    "The **F-box domain** is required for **complex formation and ubiquitination function** (e.g., ΔF-box mutants fail to promote ubiquitination of targets or to form productive complexes)."
  • FBXO16 targets the nuclear pool of beta-catenin for K48-linked polyubiquitination, suppressing Wnt/TCF transcriptional output.
    "FBXO16 physically interacts with β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output."
  • FBXO16 acts as the substrate-recognition component of a PDLIM2-containing CRL1 complex that promotes nuclear p65/RELA polyubiquitination and degradation, limiting NF-kappa-B activation.
    "Fbxo16 was identified as a substrate-recognition component in a **PDLIM2-containing CRL1 complex** that promotes p65 polyubiquitination and degradation in nuclear compartments, suppressing NF-κB activation."

Suggested Questions for Experts

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)?

Suggested Experiments

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.

Deep Research

Falcon

(FBXO16-deep-research-falcon.md)
Research Report: Human **FBXO16** (UniProt Q8IX29) — Functional Annotation Falcon Edison Scientific Literature 12 citations 2 artifacts 2026-06-13T06:28:51.705367
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000016 The requested information on FBXO16's interaction with β-catenin, its role in nuclear β-catenin ubiquitination, and domain mapping (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
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We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

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Research Report: Human FBXO16 (UniProt Q8IX29) — Functional Annotation

0) Target verification (mandatory)

The literature gathered here consistently studies FBXO16 (F-box only protein 16) as an F-box domain–containing substrate-receptor component of CRL1/SCF (CUL1–SKP1–RBX1) ubiquitin ligase complexes, matching the target identity and domain logic in UniProt (F-box domain(s) plus additional C-terminal substrate-recognition region). No evidence reviewed corresponded to a different gene with a confusingly similar symbol. (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, ji2021fbxo16mediatedhnrnplubiquitination pages 4-6)

1) Key concepts & definitions (current understanding)

1.1 F-box proteins and SCF/CRL1 E3 ligases

F-box proteins are generally understood to function as substrate-recognition receptors in SCF/CRL1 E3 ubiquitin ligase complexes, where the F-box motif mediates association with SKP1, and the cullin scaffold (CUL1) with RBX1 recruits an E2 enzyme to catalyze ubiquitin transfer to substrates. FBXO16 behaves consistently with this architecture: its F-box domain is required for assembling functional ubiquitin-ligase activity, whereas a C-terminal region mediates substrate binding/recognition. (ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, ji2021fbxo16mediatedhnrnplubiquitination pages 4-6, khan2019attenuationoftumor pages 4-6, sugimotoishige2025fbxo16mediatesdegradation pages 8-9)

1.2 What “E3 ligase substrate receptor” means for FBXO16 function

For FBXO16, the “primary function” is not to catalyze a chemical reaction like an enzyme active site; rather, it confers substrate specificity on a ubiquitin ligase complex by binding selected proteins and positioning them for polyubiquitination and usually proteasomal degradation (often via K48-linked polyubiquitin). (khan2019attenuationoftumor pages 4-6, zhang2024mir937amplificationpotentiates pages 7-10, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)

2) FBXO16 molecular function: substrates, mechanisms, and domains

2.1 Validated substrates (experimentally supported)

Across primary mechanistic studies, FBXO16 has been experimentally validated to target multiple proteins for ubiquitin-dependent degradation:

  1. β-catenin (CTNNB1): FBXO16 physically interacts with β-catenin and promotes K48-linked polyubiquitination and proteasome-mediated degradation of the nuclear pool of β-catenin, suppressing Wnt/TCF transcriptional output. (khan2019attenuationoftumor pages 1-2, khan2019attenuationoftumor pages 4-6)
  2. hnRNPL: FBXO16 assembles a canonical SCF complex via its F-box domain and targets hnRNPL for ubiquitination and degradation; substrate recognition maps to the FBXO16 C-terminus, binding the RRM3 domain of hnRNPL. (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)
  3. ULK1: In ovarian cancer models, FBXO16 binds ULK1 and promotes K48-linked polyubiquitination and reduced ULK1 protein abundance, thereby suppressing autophagy outputs. (zhang2024mir937amplificationpotentiates pages 7-10)
  4. NF-κB p65/RELA (functional substrate in immune context): Fbxo16 was identified as a substrate-recognition component in a PDLIM2-containing CRL1 complex that promotes p65 polyubiquitination and degradation in nuclear compartments, suppressing NF-κB activation. (sugimotoishige2025fbxo16mediatesdegradation pages 6-7, sugimotoishige2025fbxo16mediatesdegradation pages 8-9)

2.2 Domain logic (F-box vs. substrate-binding region)

Two consistent structure–function principles emerge:

  • The F-box domain is required for complex formation and ubiquitination function (e.g., ΔF-box mutants fail to promote ubiquitination of targets or to form productive complexes). (ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, sugimotoishige2025fbxo16mediatesdegradation pages 8-9)
  • The C-terminal region is repeatedly implicated in substrate recognition:
  • For β-catenin, a C-terminal deletion abolishes binding to β-catenin, while F-box or N-terminal deletions can retain interaction, indicating substrate binding is C-terminally mediated. (khan2019attenuationoftumor pages 4-6, khan2019attenuationoftumor pages 2-3)
  • For hnRNPL, FBXO16 binds hnRNPL via its C-terminal region to hnRNPL’s RRM3 domain. (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)
  • For ULK1, the study explicitly tests an FBXO16 ΔCTD construct in functional assays, implying CTD importance for FBXO16 inhibitory function. (zhang2024mir937amplificationpotentiates pages 7-10)

2.3 Mechanistic visualization (figure evidence)

Khan et al. provide direct figure-level evidence supporting: (i) FBXO16–β-catenin interaction, (ii) increased total and K48-linked ubiquitination of nuclear β-catenin with FBXO16 expression, and (iii) domain mapping showing the C-terminus is essential for β-catenin interaction. (khan2019attenuationoftumor media a83ab1b6)

3) Cellular localization & where FBXO16 acts

FBXO16 functional evidence strongly emphasizes nuclear contexts:

  • In glioblastoma models, FBXO16 targets the nuclear fraction of β-catenin for K48-linked polyubiquitination and degradation. (khan2019attenuationoftumor pages 1-2, khan2019attenuationoftumor pages 4-6)
  • In ovarian cancer, FBXO16 is reported as mainly nuclear and targets nuclear hnRNPL, consistent with its substrate being a predominantly nuclear RNA-binding protein. (ji2021fbxo16mediatedhnrnplubiquitination pages 4-6, ji2021fbxo16mediatedhnrnplubiquitination pages 1-2)
  • In immune signaling studies, Fbxo16 promotes p65 degradation in nuclear/intranuclear compartments and shifts p65 to an insoluble nuclear fraction prior to proteasomal degradation. (sugimotoishige2025fbxo16mediatesdegradation pages 8-9)

Taken together, FBXO16 appears to be a nuclear-relevant CRL1 substrate receptor with substrate-dependent localization (and some evidence for both cytoplasmic and nuclear presence in the NF-κB study’s discussion referencing HPA). (sugimotoishige2025fbxo16mediatesdegradation pages 7-8)

4) Pathways and biological processes regulated by FBXO16

4.1 Wnt/β-catenin signaling (tumor suppression via β-catenin turnover)

FBXO16 suppresses Wnt signaling by promoting nuclear β-catenin degradation. In glioblastoma models, this is linked to reduced expression of canonical β-catenin/TCF outputs such as c-Myc and Cyclin D1, reduced TOPFlash reporter activity, and reduced malignant phenotypes. (khan2019attenuationoftumor pages 4-6, khan2019attenuationoftumor pages 1-2)

4.2 RNA-binding protein regulation and oncogenic pathway control (hnRNPL axis)

In ovarian cancer models, FBXO16-mediated hnRNPL degradation is associated with suppression of malignant phenotypes and reduction of multiple oncogenic signaling outputs. In FBXO16 KO conditions, hnRNPL knockdown was sufficient to reverse activation of MAPK, RAS, and Wnt signaling described in that study. (ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)

4.3 Autophagy initiation (ULK1 axis)

A 2024 study identifies ULK1 as a degradation substrate of FBXO16 and links FBXO16 to autophagy suppression: FBXO16 overexpression reduces ULK1 and shifts autophagy markers (e.g., lower LC3II/I ratio, increased p62), while FBXO16 knockdown increases ULK1 protein. (zhang2024mir937amplificationpotentiates pages 7-10)

4.4 NF-κB inflammatory signaling (p65/RELA axis)

In dendritic cell contexts, Fbxo16 functions as a substrate receptor for p65 in a PDLIM2-containing CRL1 complex; Fbxo16 promotes p65 degradation and thereby limits NF-κB transactivation and pro-inflammatory cytokine expression (e.g., IL-6). (sugimotoishige2025fbxo16mediatesdegradation pages 6-7, sugimotoishige2025fbxo16mediatesdegradation pages 8-9)

5) Recent developments (prioritizing 2023–2024)

5.1 2024: MIR937 amplification → FBXO16 downregulation → ULK1 stabilization → increased autophagy

Zhang et al. (published Oct 2024 in Cell Death & Disease) propose and experimentally support a regulatory axis where MIR937 amplification increases miR-937-5p, which targets the 3′ UTR of FBXO16, reducing FBXO16 levels and thereby restricting FBXO16’s degradative effect on ULK1, promoting autophagy and proliferative capacity in high-grade serous ovarian cancer models. (zhang2024mir937amplificationpotentiates pages 7-10)

5.2 2023: disease-association and systems evidence (database aggregation)

Open Targets aggregates genetic/literature evidence linking FBXO16 to neoplasm-related terms and specific cancers (e.g., ovarian cancer, glioblastoma multiforme) and also reports associations for amyotrophic lateral sclerosis (ALS) in its evidence set. While these are not mechanistic proofs, they are useful for prioritizing disease contexts for follow-up experimentation. (OpenTargets Search: -FBXO16)

6) Current applications and real-world implementations

6.1 Biomarker and mechanistic target candidate in oncology

Primary mechanistic studies support FBXO16 as a tumor-suppressive regulator through degradation of oncogenic effectors (β-catenin, hnRNPL, ULK1-mediated autophagy), suggesting potential translational applications:

  • Biomarker concept: low FBXO16 expression can be interpreted as permissive for elevated Wnt signaling (via β-catenin) or increased autophagy (via ULK1), depending on tumor type and context. (khan2019attenuationoftumor pages 1-2, zhang2024mir937amplificationpotentiates pages 7-10)
  • Therapeutic hypothesis: strategies that restore FBXO16 function or mimic its substrate-degradation effects might suppress tumor growth programs mediated by β-catenin, hnRNPL, or ULK1. These are still preclinical hypotheses grounded in cell and xenograft models rather than clinical trials. (khan2019attenuationoftumor pages 4-6, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9, zhang2024mir937amplificationpotentiates pages 7-10)

6.2 Targeting upstream regulators (noncoding RNA axes)

The 2024 MIR937/miR-937-5p → FBXO16 → ULK1 axis provides a concrete example of a potentially druggable regulatory layer: blocking miR-937-5p or restoring FBXO16 could reduce ULK1-mediated autophagy that supports tumor cell fitness. (zhang2024mir937amplificationpotentiates pages 7-10)

7) Expert interpretation and analysis (evidence-weighted)

7.1 Most confident functional statement

The strongest, repeatedly supported functional annotation is:

FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.

This is supported by multiple primary mechanistic datasets across different substrates and contexts (β-catenin, hnRNPL, ULK1; nuclear p65 in immune context). (khan2019attenuationoftumor pages 4-6, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9, zhang2024mir937amplificationpotentiates pages 7-10, sugimotoishige2025fbxo16mediatesdegradation pages 8-9)

7.2 Substrate selectivity and context dependence

FBXO16 substrates appear context-dependent (tumor type, cell state, and possibly binding partners like PDLIM2). For example, ULK1 is prominent in one ovarian cancer mechanism, while hnRNPL is emphasized in another; the ULK1-focused study notes hnRNPL is not altered in that specific context, implying separable substrate modules. (zhang2024mir937amplificationpotentiates pages 7-10)

7.3 C-terminal substrate-recognition as a unifying mechanistic theme

Independent substrate-mapping experiments converge on the FBXO16 C-terminus as a key substrate-binding interface (β-catenin, hnRNPL; likely ULK1). This suggests that perturbations in the C-terminal region (mutation, truncation, binding competition) could broadly disable FBXO16 substrate recognition even if SCF assembly remains intact. (khan2019attenuationoftumor pages 4-6, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)

8) Statistics and quantitative data from recent/primary studies

  • Ovarian cancer clinical specimens (hnRNPL axis): In 68 ovarian cancer specimens, FBXO16 expression was negatively correlated with hnRNPL (χ² = 14.81, P < 0.001). (ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)
  • In vivo tumor growth (hnRNPL recognition domain): In SKOV3 xenografts (injection 1×10^7 cells; n = 5 mice), expression of hnRNPL lacking the FBXO16-recognition domain (ΔRRM3) increased tumor growth (P < 0.001), consistent with impaired FBXO16-mediated hnRNPL degradation promoting tumor growth. (ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)
  • β-catenin nuclear puncta: FBXO16 overexpression produced an approximately 4-fold reduction in nuclear RFP-β-catenin speckles in glioblastoma models, alongside reduced Wnt reporter output and downstream targets. (khan2019attenuationoftumor pages 4-6)
  • Migration phenotype: FBXO16 overexpression reduced migration by ~30% (P ≤ 0.008) in the glioblastoma study excerpt. (khan2019attenuationoftumor pages 4-6)
  • Disease association evidence counts (Open Targets): Open Targets lists FBXO16 associations for several diseases with evidence_size = 5 in its returned summary for diseases including glioblastoma multiforme, neoplasm, cervical carcinoma, ALS, and ovarian cancer. (OpenTargets Search: -FBXO16)

9) Evidence map summary table

The following table consolidates substrates, mechanisms, domains, localization, contexts, and key quantitative points.

Substrate/Interactor Evidence type (co-IP, ubiquitination, degradation, functional assay) Ubiquitin linkage / degradation mechanism Required FBXO16 domain(s) Cellular compartment Biological context (cell type/cancer) Key quantitative data (n, fold-changes, p-values) Publication (authors, journal, year, date) URL Citation context ID
β-catenin (CTNNB1) IP/co-IP interaction in RANG-2 and LN229; nuclear-fraction ubiquitination assays; MG132 rescue; TOPFlash Wnt reporter; migration/proliferation/xenograft assays K48-linked polyubiquitination of nuclear β-catenin followed by proteasome-dependent degradation; reported GSK3β-independent C-terminal region required for β-catenin interaction; ΔC loses binding, while ΔF and N-terminal deletion retain interaction Predominantly nuclear β-catenin pool Human glioblastoma models (RANG-2, LN229; xenografts) ~4-fold reduction in nuclear RFP-β-catenin speckles with FBXO16 overexpression; ~30% reduced migration (P≤0.008); decreased TOPFlash, c-Myc, Cyclin D1; qRT-PCR cohort glioma n=11 vs normal brain n=4; xenograft tumor volume ~800 mm^3 ±71.6 in model context; n=3 for some assays, P≤0.001 Khan, Muzumdar, Shiras; Neoplasia; 2019; Jan https://doi.org/10.1016/j.neo.2018.11.005 (khan2019attenuationoftumor pages 4-6, khan2019attenuationoftumor pages 1-2, khan2019attenuationoftumor pages 2-3, khan2019attenuationoftumor media a83ab1b6)
hnRNPL BioGRID-guided candidate identification; co-IP and GST pull-down; TUBE2 ubiquitination enrichment; CHX half-life; MG132 rescue; in vitro ubiquitination with Cul1-Skp1-Rbx1 + FBXO16; rescue/phenocopy functional assays SCF/CUL1-SKP1-RBX1-dependent ubiquitination and proteasomal degradation of hnRNPL F-box required for ubiquitination activity; C-terminal region required for substrate recognition; binds hnRNPL RRM3 domain FBXO16 reported mainly nuclear; hnRNPL mainly nuclear Human ovarian cancer cells; SKOV3 xenograft Negative FBXO16-hnRNPL correlation in 68 ovarian cancer specimens (χ²=14.81, P<0.001); hnRNPL ΔRRM3 xenograft using 1×10^7 cells, n=5 mice, significantly increased tumor growth (P<0.001); FBXO16 loss increased proliferation, clonogenicity, invasion Ji et al.; Cell Death & Disease; 2021; Jul https://doi.org/10.1038/s41419-021-04040-9 (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, ji2021fbxo16mediatedhnrnplubiquitination pages 4-6, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)
ULK1 Co-IP/in vitro interaction; ubiquitination assays; FBXO16 knockdown/overexpression; autophagy and proliferation assays; truncation-mutant testing K48-linked polyubiquitination of ULK1 with proteasomal targeting; FBXO16 suppresses ULK1-dependent autophagy C-terminal region implicated based on ΔCTD testing in binding and functional assays Not explicitly localized in excerpt; mechanism studied in cellular protein turnover/autophagy context Human high-grade serous ovarian cancer models FBXO16 knockdown increased ULK1 protein while not affecting ATG7/ATG13/Beclin-1; FBXO16 overexpression decreased ULK1, lowered LC3II/I ratio, increased p62; no cohort HR/effect size reported in excerpt Zhang et al.; Cell Death & Disease; 2024; Oct https://doi.org/10.1038/s41419-024-07120-8 (zhang2024mir937amplificationpotentiates pages 7-10)
NF-κB p65 (RELA) siRNA screen of 39 Fbxo genes; co-IP with PDLIM2/CUL1/SKP1; polyubiquitination assays; nuclear fractionation; ELAM-1 luciferase; knockdown/deficiency functional assays Polyubiquitination and proteasomal degradation of p65 within a PDLIM2-containing CRL1/SCF-like complex; loss of Fbxo16 increases nuclear p65 and inflammatory cytokines F-box domain required for CUL1/PDLIM2 complex formation and p65 polyubiquitination; ΔF mutant impaired Nuclear/intranuclear, including insoluble nuclear fraction Dendritic cells; HEK293T, BMDCs, MEFs; inflammatory signaling rather than cancer Screened 39 Fbxo genes; Fbxo16 deficiency caused striking augmentation of LPS-induced IL-6 and enhanced nuclear p65; WT but not ΔF suppressed NF-κB luciferase activity; no hazard ratios reported Sugimoto-Ishige, Jodo, Tanaka; Frontiers in Immunology; 2025; Jun https://doi.org/10.3389/fimmu.2025.1524110 (sugimotoishige2025fbxo16mediatesdegradation pages 8-9, sugimotoishige2025fbxo16mediatesdegradation pages 6-7, sugimotoishige2025fbxo16mediatesdegradation pages 12-13, sugimotoishige2025fbxo16mediatesdegradation pages 7-8, sugimotoishige2025fbxo16mediatesdegradation pages 5-6)
SKP1 / CUL1 / RBX1 (SCF components) Interaction/co-complex evidence; in vitro ubiquitination with Cul1-Skp1-Rbx1 plus FBXO16; co-IP with CUL1/SKP1; dominant-negative CUL1 effects Supports FBXO16 as the substrate-recognition module of canonical SCF/CRL1 E3 ligase rather than a substrate itself F-box domain mediates SCF assembly/function Nuclear context emphasized in ovarian cancer and p65 studies; broader cytoplasmic+nuclear localization also reported Human ovarian cancer cells; HEK293T; dendritic cell signaling Dominant-negative CUL1 caused hnRNPL accumulation; Fbxo16 binds CUL1/SKP1 but not CUL2/CUL3 in immune study; quantitative interaction values not provided Ji et al.; Cell Death & Disease; 2021; Jul; Sugimoto-Ishige et al.; Frontiers in Immunology; 2025; Jun https://doi.org/10.1038/s41419-021-04040-9 ; https://doi.org/10.3389/fimmu.2025.1524110 (ji2021fbxo16mediatedhnrnplubiquitination pages 6-8, ji2021fbxo16mediatedhnrnplubiquitination pages 4-6, sugimotoishige2025fbxo16mediatesdegradation pages 6-7)
PDLIM2 Co-IP/complex assembly evidence in p65-targeting study Partner in a PDLIM2-containing CRL1 complex that enables p65 recruitment, polyubiquitination, and degradation F-box domain needed for proper complex formation with CUL1/PDLIM2 Nuclear/intranuclear Dendritic cells; HEK293T reconstitution system Fbxo16 knockdown was the key hit reverting PDLIM2-dependent p65 decrease in screen-derived follow-up; no explicit effect size in excerpt Sugimoto-Ishige, Jodo, Tanaka; Frontiers in Immunology; 2025; Jun https://doi.org/10.3389/fimmu.2025.1524110 (sugimotoishige2025fbxo16mediatesdegradation pages 8-9, sugimotoishige2025fbxo16mediatesdegradation pages 6-7, sugimotoishige2025fbxo16mediatesdegradation pages 5-6)

Table: This table compiles experimentally supported evidence for human FBXO16 (UniProt Q8IX29), emphasizing validated substrates, SCF/CRL1 complex partners, domain requirements, compartment, biological context, and quantitative findings. It is useful as a compact functional-annotation map grounded in primary literature and citeable context IDs.

10) Limitations and open questions

  1. UniProt accession reporting: The primary papers reviewed typically refer to FBXO16 by gene/protein name rather than explicitly stating UniProt Q8IX29; identity matching is therefore based on symbol/function/domain congruence rather than explicit accession mention. (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, khan2019attenuationoftumor pages 4-6)
  2. Incomplete substrate landscape: While β-catenin, hnRNPL, ULK1, and p65 have evidence, the full substrate repertoire and recognition motifs remain incompletely defined. Context-dependent substrate selection is likely. (zhang2024mir937amplificationpotentiates pages 7-10)
  3. Clinical translation: Evidence is largely mechanistic and preclinical (cell and xenograft models); no FBXO16-directed therapies or clinical trials were identified in the gathered evidence.

Key primary sources (with publication dates and URLs)

  • Khan M, Muzumdar D, Shiras A. Attenuation of tumor suppressive function of FBXO16 ubiquitin ligase activates Wnt signaling in glioblastoma. Neoplasia. Jan 2019. https://doi.org/10.1016/j.neo.2018.11.005 (khan2019attenuationoftumor pages 4-6, khan2019attenuationoftumor media a83ab1b6)
  • Ji M et al. FBXO16-mediated hnRNPL ubiquitination and degradation plays a tumor suppressor role in ovarian cancer. Cell Death & Disease. Jul 2021. https://doi.org/10.1038/s41419-021-04040-9 (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2, ji2021fbxo16mediatedhnrnplubiquitination pages 8-9)

  • Zhang Z et al. MIR937 amplification potentiates ovarian cancer progression by attenuating FBXO16 inhibition on ULK1-mediated autophagy. Cell Death & Disease. Oct 2024. https://doi.org/10.1038/s41419-024-07120-8 (zhang2024mir937amplificationpotentiates pages 7-10)

  • Open Targets Platform (disease–target association aggregation for FBXO16). Accessed via tool output. https://platform.opentargets.org/ (OpenTargets Search: -FBXO16)

References

  1. (ji2021fbxo16mediatedhnrnplubiquitination pages 1-2): Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Jing Ji, Wei Liu, and Bin Liu. Fbxo16-mediated hnrnpl ubiquitination and degradation plays a tumor suppressor role in ovarian cancer. Cell Death & Disease, Jul 2021. URL: https://doi.org/10.1038/s41419-021-04040-9, doi:10.1038/s41419-021-04040-9. This article has 34 citations and is from a peer-reviewed journal.

  2. (ji2021fbxo16mediatedhnrnplubiquitination pages 6-8): Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Jing Ji, Wei Liu, and Bin Liu. Fbxo16-mediated hnrnpl ubiquitination and degradation plays a tumor suppressor role in ovarian cancer. Cell Death & Disease, Jul 2021. URL: https://doi.org/10.1038/s41419-021-04040-9, doi:10.1038/s41419-021-04040-9. This article has 34 citations and is from a peer-reviewed journal.

  3. (ji2021fbxo16mediatedhnrnplubiquitination pages 4-6): Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Jing Ji, Wei Liu, and Bin Liu. Fbxo16-mediated hnrnpl ubiquitination and degradation plays a tumor suppressor role in ovarian cancer. Cell Death & Disease, Jul 2021. URL: https://doi.org/10.1038/s41419-021-04040-9, doi:10.1038/s41419-021-04040-9. This article has 34 citations and is from a peer-reviewed journal.

  4. (khan2019attenuationoftumor pages 4-6): Mohsina Khan, Dattatraya Muzumdar, and Anjali Shiras. Attenuation of tumor suppressive function of fbxo16 ubiquitin ligase activates wnt signaling in glioblastoma. Jan 2019. URL: https://doi.org/10.1016/j.neo.2018.11.005, doi:10.1016/j.neo.2018.11.005. This article has 35 citations and is from a domain leading peer-reviewed journal.

  5. (sugimotoishige2025fbxo16mediatesdegradation pages 8-9): Akiko Sugimoto-Ishige, Aya Jodo, and Takashi Tanaka. Fbxo16 mediates degradation of nf-κb p65 subunit and inhibits inflammatory response in dendritic cells. Frontiers in Immunology, Jun 2025. URL: https://doi.org/10.3389/fimmu.2025.1524110, doi:10.3389/fimmu.2025.1524110. This article has 3 citations and is from a peer-reviewed journal.

  6. (zhang2024mir937amplificationpotentiates pages 7-10): Zhen Zhang, Xinkui Liu, Chu Chu, Yingjie Zhang, Wei Li, Xiaoyan Yu, Qiaoqiao Han, Haoyu Sun, Yunhong Zhang, Xiaoxiao Zhu, Liang Chen, Ran Wei, Nannan Fan, Miaomiao Zhou, and Xia Li. Mir937 amplification potentiates ovarian cancer progression by attenuating fbxo16 inhibition on ulk1-mediated autophagy. Cell Death & Disease, Oct 2024. URL: https://doi.org/10.1038/s41419-024-07120-8, doi:10.1038/s41419-024-07120-8. This article has 5 citations and is from a peer-reviewed journal.

  7. (ji2021fbxo16mediatedhnrnplubiquitination pages 8-9): Mei Ji, Zhao Zhao, Yue Li, Penglin Xu, Jia Shi, Zhe Li, Kaige Wang, Xiaotian Huang, Jing Ji, Wei Liu, and Bin Liu. Fbxo16-mediated hnrnpl ubiquitination and degradation plays a tumor suppressor role in ovarian cancer. Cell Death & Disease, Jul 2021. URL: https://doi.org/10.1038/s41419-021-04040-9, doi:10.1038/s41419-021-04040-9. This article has 34 citations and is from a peer-reviewed journal.

  8. (khan2019attenuationoftumor pages 1-2): Mohsina Khan, Dattatraya Muzumdar, and Anjali Shiras. Attenuation of tumor suppressive function of fbxo16 ubiquitin ligase activates wnt signaling in glioblastoma. Jan 2019. URL: https://doi.org/10.1016/j.neo.2018.11.005, doi:10.1016/j.neo.2018.11.005. This article has 35 citations and is from a domain leading peer-reviewed journal.

  9. (sugimotoishige2025fbxo16mediatesdegradation pages 6-7): Akiko Sugimoto-Ishige, Aya Jodo, and Takashi Tanaka. Fbxo16 mediates degradation of nf-κb p65 subunit and inhibits inflammatory response in dendritic cells. Frontiers in Immunology, Jun 2025. URL: https://doi.org/10.3389/fimmu.2025.1524110, doi:10.3389/fimmu.2025.1524110. This article has 3 citations and is from a peer-reviewed journal.

  10. (khan2019attenuationoftumor pages 2-3): Mohsina Khan, Dattatraya Muzumdar, and Anjali Shiras. Attenuation of tumor suppressive function of fbxo16 ubiquitin ligase activates wnt signaling in glioblastoma. Jan 2019. URL: https://doi.org/10.1016/j.neo.2018.11.005, doi:10.1016/j.neo.2018.11.005. This article has 35 citations and is from a domain leading peer-reviewed journal.

  11. (khan2019attenuationoftumor media a83ab1b6): Mohsina Khan, Dattatraya Muzumdar, and Anjali Shiras. Attenuation of tumor suppressive function of fbxo16 ubiquitin ligase activates wnt signaling in glioblastoma. Jan 2019. URL: https://doi.org/10.1016/j.neo.2018.11.005, doi:10.1016/j.neo.2018.11.005. This article has 35 citations and is from a domain leading peer-reviewed journal.

  12. (sugimotoishige2025fbxo16mediatesdegradation pages 7-8): Akiko Sugimoto-Ishige, Aya Jodo, and Takashi Tanaka. Fbxo16 mediates degradation of nf-κb p65 subunit and inhibits inflammatory response in dendritic cells. Frontiers in Immunology, Jun 2025. URL: https://doi.org/10.3389/fimmu.2025.1524110, doi:10.3389/fimmu.2025.1524110. This article has 3 citations and is from a peer-reviewed journal.

  13. (OpenTargets Search: -FBXO16): Open Targets Query (-FBXO16, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  14. (sugimotoishige2025fbxo16mediatesdegradation pages 12-13): Akiko Sugimoto-Ishige, Aya Jodo, and Takashi Tanaka. Fbxo16 mediates degradation of nf-κb p65 subunit and inhibits inflammatory response in dendritic cells. Frontiers in Immunology, Jun 2025. URL: https://doi.org/10.3389/fimmu.2025.1524110, doi:10.3389/fimmu.2025.1524110. This article has 3 citations and is from a peer-reviewed journal.

  15. (sugimotoishige2025fbxo16mediatesdegradation pages 5-6): Akiko Sugimoto-Ishige, Aya Jodo, and Takashi Tanaka. Fbxo16 mediates degradation of nf-κb p65 subunit and inhibits inflammatory response in dendritic cells. Frontiers in Immunology, Jun 2025. URL: https://doi.org/10.3389/fimmu.2025.1524110, doi:10.3389/fimmu.2025.1524110. This article has 3 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. khan2019attenuationoftumor pages 4-6
  2. khan2019attenuationoftumor pages 1-2
  3. khan2019attenuationoftumor pages 2-3
  4. https://doi.org/10.1016/j.neo.2018.11.005
  5. https://doi.org/10.1038/s41419-021-04040-9
  6. https://doi.org/10.1038/s41419-024-07120-8
  7. https://doi.org/10.3389/fimmu.2025.1524110
  8. https://platform.opentargets.org/
  9. https://doi.org/10.1038/s41419-021-04040-9,
  10. https://doi.org/10.1016/j.neo.2018.11.005,
  11. https://doi.org/10.3389/fimmu.2025.1524110,
  12. https://doi.org/10.1038/s41419-024-07120-8,

📚 Additional Documentation

Pn Notes

(FBXO16-pn-notes.md)

FBXO16 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q8IX29
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 1

PN Consistency Summary

  • Consistency: Consistent. DR ↔ YAML agree FBXO16 is a nuclear-acting CRL1/SCF substrate receptor driving K48-linked degradation of beta-catenin, hnRNPL, ULK1, RELA/p65. Review ACCEPTs SCF complex (GO:0019005) and SCF-dependent catabolism (GO:0031146); GO:1990756 is the core MF, matching PN.
  • PN story / NEW pressure: PN asserts the adaptor MF. GO:1990756 (verified real) is NOT in GOA for FBXO16 — but, as with FBXO8, it appears only in core_functions, not as a NEW existing_annotation; FBXO16 has NO MF annotation in its existing_annotations at all (only protein binding IPI + two NAS CC/BP). So the adaptor MF is a defensible ADD that the review states but does not formally annotate. Validated substrates present (not substrate-less).
  • Evidence alignment: PN cites only 15340381. Review uses PMID:32296183 (binary interactome, LOW), 34445249 (SCF/ComplexPortal CPX-7926), plus Falcon substrate leads (Khan 2019, Ji 2021, Zhang 2024, Sugimoto-Ishige 2025). Expansion, no conflict.
  • Verdict: Consistent; PN adaptor mapping appropriate and matches review core function.

Full Consistency Review

  • UniProt: Q8IX29 · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: subtype/type no_mapping; group Cul1 substrate receptor=mapped / ok_for_propagation_to_go → GO:1990756 (new_to_goa); class context_only/too_broad (GO:0061630).
  • Consistency: Consistent. DR ↔ YAML agree FBXO16 is a nuclear-acting CRL1/SCF substrate receptor driving K48-linked degradation of beta-catenin, hnRNPL, ULK1, RELA/p65. Review ACCEPTs SCF complex (GO:0019005) and SCF-dependent catabolism (GO:0031146); GO:1990756 is the core MF, matching PN.
  • PN story / NEW pressure: PN asserts the adaptor MF. GO:1990756 (verified real) is NOT in GOA for FBXO16 — but, as with FBXO8, it appears only in core_functions, not as a NEW existing_annotation; FBXO16 has NO MF annotation in its existing_annotations at all (only protein binding IPI + two NAS CC/BP). So the adaptor MF is a defensible ADD that the review states but does not formally annotate. Validated substrates present (not substrate-less).
  • Mapping strategy: Gene does not change the node; status/scope correct. PN-projected GO:1990756 at right altitude. Class GO:0061630 too_broad. A nuclear-localization theme (DR) is not yet annotated but PN does not assert it either.
  • Evidence alignment: PN cites only 15340381. Review uses PMID:32296183 (binary interactome, LOW), 34445249 (SCF/ComplexPortal CPX-7926), plus Falcon substrate leads (Khan 2019, Ji 2021, Zhang 2024, Sugimoto-Ishige 2025). Expansion, no conflict.
  • Verdict: Consistent; PN adaptor mapping appropriate and matches review core function.
  • Recommended edits: [YAML] consider adding GO:1990756 as a NEW MF existing_annotation (currently FBXO16 carries no MF annotation; the adaptor activity lives only in core_functions) — mirrors the explicit NEW done for FBXO15. [MAP] none.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO16/FBXO16-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | other

  • UniProt: Q8IX29
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: (none)
  • PN references (titles):
    • 15340381 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q8IX29
gene_symbol: FBXO16
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: Q8IX29-1
- name: '2'
  id: Q8IX29-2
  sequence_note: VSP_045600
existing_annotations:
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
      supporting_text: 'Q8IX29; P25800: LMO1; NbExp=3; IntAct=EBI-12063229, EBI-8639312;'
    - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
      supporting_text: 'Q8IX29; Q9UKK6: NXT1; NbExp=5; IntAct=EBI-12063229, EBI-301889;'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
      supporting_text: >-
        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.
    - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
      supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.'
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
      supporting_text: >-
        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.
    - reference_id: file:human/FBXO16/FBXO16-deep-research-falcon.md
      supporting_text: FBXO16 physically interacts with β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output.
core_functions:
- description: >-
    Substrate-recognition (F-box) component of an SCF/CRL1 E3 ubiquitin ligase
    complex that binds specific substrate proteins (e.g. nuclear
    beta-catenin/CTNNB1, hnRNPL, RELA/p65, ULK1) and presents them, via SKP1 and
    the CUL1-RBX1 catalytic core, for polyubiquitination and proteasomal
    degradation. Acts as a ubiquitin-ligase substrate adaptor rather than the
    catalytic ligase.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  supported_by:
  - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
    supporting_text: >-
      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.
  - reference_id: file:human/FBXO16/FBXO16-uniprot.txt
    supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.'
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
- question: >-
    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)?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
- description: >-
    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.
references:
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      High-throughput yeast two-hybrid binary interactome map that records
      FBXO16 interactions (e.g. LMO1, MORF4L1, MORF4L2, NXT1, TRIM54) deposited
      in IntAct.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available. Source of the GO:0005515 bare protein binding
      annotations; high-throughput binary interactome, not FBXO16-specific
      functional characterization.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: >-
      Review of SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes and their
      role in genome/chromosome stability; cited by ComplexPortal as supporting
      reference for SCF complex membership and SCF-dependent proteasomal
      degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only (full_text_available: false). General SCF review used by
      ComplexPortal as the NAS reference for FBXO16's SCF complex membership and
      SCF-dependent catabolic process annotations; supports the family-level
      mechanism rather than FBXO16-specific substrate claims.
- id: file:human/FBXO16/FBXO16-deep-research-falcon.md
  title: Falcon deep research report for human FBXO16
  findings:
  - statement: FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.
    supporting_text: '**FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.**'
  - statement: The FBXO16 F-box domain is required for ligase complex formation while its C-terminal region mediates substrate recognition (e.g. binding the hnRNPL RRM3 domain; C-terminus essential for beta-catenin binding).
    supporting_text: The **F-box domain** is required for **complex formation and ubiquitination function** (e.g., ΔF-box mutants fail to promote ubiquitination of targets or to form productive complexes).
  - statement: FBXO16 targets the nuclear pool of beta-catenin for K48-linked polyubiquitination, suppressing Wnt/TCF transcriptional output.
    supporting_text: FBXO16 physically interacts with β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output.
  - statement: FBXO16 acts as the substrate-recognition component of a PDLIM2-containing CRL1 complex that promotes nuclear p65/RELA polyubiquitination and degradation, limiting NF-kappa-B activation.
    supporting_text: Fbxo16 was identified as a substrate-recognition component in a **PDLIM2-containing CRL1 complex** that promotes p65 polyubiquitination and degradation in nuclear compartments, suppressing NF-κB activation.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      Falcon synthesis anchored on real primary studies: Khan et al. 2019
      (beta-catenin/glioblastoma), Ji et al. 2021 (hnRNPL/ovarian cancer),
      Zhang et al. 2024 (MIR937/ULK1/autophagy, Cell Death Dis), and
      Sugimoto-Ishige et al. 2025 (p65/PDLIM2-CRL1). These corroborate and extend
      the substrate set already in this review and add a nuclear-localization theme
      and C-terminal substrate-binding domain logic. Falcon cites author-year/DOIs
      not PMIDs and the papers are not in the local cache, so substrate and
      localization claims are treated as strong leads (UNVERIFIED) pending curator
      confirmation; no substrate-specific or nuclear-location GO terms are added on
      this basis alone.