FBXL8 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: Q96CD0
- 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: FBXL8 (F-box/LRR-repeat protein 8, FBL8) is a member of the FBXL subfamily of F-box proteins. It has an N-terminal F-box domain through which it docks onto the SKP1 adaptor and, via SKP1, onto CUL1 and the catalytic RING subunit RBX1, assembling a Cullin-RING (SCF) E3 ubiquitin ligase in which the F-box protein serves as the substrate-recognition subunit. Despite the "LRR" in its name, UniProt notes that FBXL8 does not actually contain canonical leucine-rich repeats; nonetheless its C-terminal substrate-binding region is functionally required for substrate engagement (deletion of either the F-box or the C-terminal region abolishes substrate turnover). FBXL8 acts as the substrate-recognition subunit of SCF-FBXL8 and targets several substrates in a strongly context-dependent manner: it promotes ubiquitination and proteasomal degradation of the tumor suppressor p53 (in colorectal cancer), of Thr283- phosphorylated cyclin D3 (CCND3) (in lymphoma), of Snail1 (in post-myocardial- infarction cardiac fibroblasts, dampening RhoA signaling and myofibroblast differentiation), and of unphosphorylated c-MYC (a distinct c-MYC pool from that controlled by FBXW7, with reported heterotypic K48/K63 chains); CCND2 and IRF5 are additional candidate substrates accumulating upon FBXL8 knockdown. Reported localization is predominantly cytoplasmic (loss of FBXL8 causes nuclear c-MYC accumulation), and in heart FBXL8 is enriched in cardiac fibroblasts. Its net effect is context-dependent rather than uniformly oncogenic or tumor-suppressive: oncogenic in colorectal and breast cancer, but tumor-suppressive in lymphoma and anti-fibrotic after myocardial infarction.
- Existing/core annotation action counts: ACCEPT: 1; KEEP_AS_NON_CORE: 17
PN Consistency Summary
- Consistency: Mostly consistent, with one structural gap. Review, PN annotation, and node mapping agree FBXL8 is an SCF substrate receptor. Non-canonical F-box: UniProt notes FBXL8 does NOT contain canonical leucine-rich repeats despite the "LRR" name — yet the PN places it under the
...|F-box|LRR subtype. The review captures this caveat in its description; the PN subtype label is therefore mildly inaccurate for this member (subtype is no_mapping, so no propagation harm). Falcon substrates (p53, phospho-Thr283 CCND3, Snail1, unphospho c-MYC) are UNVERIFIED leads, correctly not added as GO terms.
- PN story / NEW pressure: PN asserts the generic adaptor MF. FBXL8 GOA has NO MF beyond
protein binding (SKP1) and no SCF-process IDA. The review's core_functions assigns GO:1990756, but — unlike FBXL7/FBXL12 — it is NOT added as an action: NEW entry in existing_annotations. This is the one batch-pattern deviation: the adaptor MF that PN projects as new_to_goa is endorsed in core_functions but never materialized as a reviewable annotation. Conclusion: ADD GO:1990756 as NEW to existing_annotations for parity.
- Evidence alignment: PN cites only "15340381/rev"; review uses SKP1 interactome PMIDs + PMID:33234069 + falcon leads. No PMID overlap with placeholder.
- Verdict: MAPPING CONSISTENT but YAML gap. Recommended edits: [YAML] add
GO:1990756 as action: NEW in FBXL8 existing_annotations (mirror FBXL7/FBXL12) so the PN-projected adaptor MF is materialized; [MAP] consider noting the non-canonical (no-LRR) status on the F-box|LRR subtype for FBXL8.
Full Consistency Review
- UniProt: Q96CD0 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
- PN placement:
UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group-level mapped / ok_for_propagation_to_go / GO:1990756; class context_only / too_broad / GO:0061630.
- Consistency: Mostly consistent, with one structural gap. Review, PN annotation, and node mapping agree FBXL8 is an SCF substrate receptor. Non-canonical F-box: UniProt notes FBXL8 does NOT contain canonical leucine-rich repeats despite the "LRR" name — yet the PN places it under the
...|F-box|LRR subtype. The review captures this caveat in its description; the PN subtype label is therefore mildly inaccurate for this member (subtype is no_mapping, so no propagation harm). Falcon substrates (p53, phospho-Thr283 CCND3, Snail1, unphospho c-MYC) are UNVERIFIED leads, correctly not added as GO terms.
- PN story / NEW pressure: PN asserts the generic adaptor MF. FBXL8 GOA has NO MF beyond
protein binding (SKP1) and no SCF-process IDA. The review's core_functions assigns GO:1990756, but — unlike FBXL7/FBXL12 — it is NOT added as an action: NEW entry in existing_annotations. This is the one batch-pattern deviation: the adaptor MF that PN projects as new_to_goa is endorsed in core_functions but never materialized as a reviewable annotation. Conclusion: ADD GO:1990756 as NEW to existing_annotations for parity.
- Mapping strategy: Gene does not change the group GO:1990756 (defensible on F-box + SKP1 grounds). FLAGS: (1) non-canonical F-box (no true LRRs) — PN
|LRR subtype label is a misnomer here; (2) no PMID-validated substrate in existing_annotations — adaptor MF is inferred-only. Scope/status otherwise correct.
- Evidence alignment: PN cites only "15340381/rev"; review uses SKP1 interactome PMIDs + PMID:33234069 + falcon leads. No PMID overlap with placeholder.
- Verdict: MAPPING CONSISTENT but YAML gap. Recommended edits: [YAML] add
GO:1990756 as action: NEW in FBXL8 existing_annotations (mirror FBXL7/FBXL12) so the PN-projected adaptor MF is materialized; [MAP] consider noting the non-canonical (no-LRR) status on the F-box|LRR subtype for FBXL8.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-13
- review_yaml: genes/human/FBXL8/FBXL8-ai-review.yaml
- PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR
- UniProt: Q96CD0
- In branches: UPS
- Signature domains: IPR001810
- Auxiliary domains: IPR032675
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR
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.