EIF4E2 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: O60573
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-07c
- Batch change status: added
Source Files Checked
Deep Research Files
- No
*-deep-research*.md file found in this gene directory.
AIGR Review Snapshot
- Description: EIF4E2 (eIF4E homologous protein, 4EHP) is a class II member of the eIF4E cap-binding protein family. It recognizes and binds the 7-methylguanosine (m7G) mRNA 5' cap but, unlike the canonical eIF4E, cannot bind the scaffold eIF4G; it therefore competes with eIF4E for the cap and blocks assembly of the eIF4F initiation complex, acting as a repressor of cap-dependent translation initiation rather than a promoter of it. 4EHP is the catalytic-cap-binding core of the 4EHP-GIGYF2 translational-repressor module: bound to GIGYF2 (and ZNF598/DDX6) it sequesters the cap of specific mRNAs to suppress their translation, including as part of ribosome-associated quality control, where it lowers the translational load on messages that cause ribosome stalling. 4EHP is also an integral component of miRNA-mediated silencing, contributing cap-binding activity that, via 4E-T and the CCR4-NOT complex, represses translation of miRNA targets, and it mediates miR-34a- directed negative-feedback control of IFNB1 (type I interferon) production - a circuit co-opted by SARS-CoV-2 nsp2. It localizes to the cytoplasm and to P-bodies and is itself a substrate for ubiquitylation by the RBR E3 ligase ARIH1/HHARI.
- Existing/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 21; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 3; REMOVE: 1
PN Consistency Summary
- Consistency: Mostly consistent on biology but with a sharp, important divergence on one node. Deep research, notes, and review agree: 4EHP is a cap-binding REPRESSOR that cannot bind eIF4G and is NOT a productive eIF4F component; it acts in the 4EHP-GIGYF1/2 RQC/repression module. The review explicitly REMOVEs GO:0016281 (eukaryotic translation initiation factor 4F complex, IBA) and MARK_AS_OVER_ANNOTATED GO:0006413 (translational initiation) as misleading family-level transfers. The PN-node mapping for the "eIF4F complex" type, however, maps to exactly GO:0016281 and the initiation group to GO:0006413 — the two terms the review rejects/downgrades. Direct contradiction at the eIF4F-complex node.
- PN story / NEW pressure: PN's RQC framing (GO:0006515, verified real) is fully borne out — review independently asserts negative regulation of translational initiation (GO:0045947, IDA) and rescue of stalled cytosolic ribosome (GO:0072344, IDA) for the RQC module. GO:0006515 is broader than these but defensible as an RQC umbrella; already captured (more specifically) by the review.
- Evidence alignment: PN dossier lists no reference titles for EIF4E2; alignment is via projected terms. Review's RQC PMIDs (32726578, 35878012, 22751931, 33053355) cover the same repression/RQC biology the GO:0006515 node encodes. No PMID divergence; the only conflict is term-level (GO:0016281).
- Verdict: Biology consistent; one node-level contradiction (PN GO:0016281 vs review REMOVE). RQC story already captured more precisely. Recommended edits: [MAP] flag the EIF4E2 "eIF4F complex" type→GO:0016281 projection as inappropriate (4EHP cannot bind eIF4G / is not an eIF4F component — see review REMOVE of GO:0016281); do not propagate GO:0016281 to O60573.
Full Consistency Review
- UniProt: O60573 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
- PN placement:
Translation|Cytosolic translation|Translation initiation|eIF4F complex AND Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: initiation type=mapped→GO:0016281 (eIF4F complex); initiation group=mapped→GO:0006413; RQC group=mapped→GO:0006515; RQC type=no_mapping; class/branch context_only (GO:0002181/GO:0006412 too_broad).
- Consistency: Mostly consistent on biology but with a sharp, important divergence on one node. Deep research, notes, and review agree: 4EHP is a cap-binding REPRESSOR that cannot bind eIF4G and is NOT a productive eIF4F component; it acts in the 4EHP-GIGYF1/2 RQC/repression module. The review explicitly REMOVEs GO:0016281 (eukaryotic translation initiation factor 4F complex, IBA) and MARK_AS_OVER_ANNOTATED GO:0006413 (translational initiation) as misleading family-level transfers. The PN-node mapping for the "eIF4F complex" type, however, maps to exactly GO:0016281 and the initiation group to GO:0006413 — the two terms the review rejects/downgrades. Direct contradiction at the eIF4F-complex node.
- PN story / NEW pressure: PN's RQC framing (GO:0006515, verified real) is fully borne out — review independently asserts negative regulation of translational initiation (GO:0045947, IDA) and rescue of stalled cytosolic ribosome (GO:0072344, IDA) for the RQC module. GO:0006515 is broader than these but defensible as an RQC umbrella; already captured (more specifically) by the review.
- Mapping strategy: The "eIF4F complex" type→GO:0016281 mapping is wrong for 4EHP and should be revisited at the PN level: 4EHP is a class-II eIF4E paralog that does not assemble into eIF4F. The PN node groups true eIF4F components, but projecting GO:0016281 onto EIF4E2 contradicts curated biology. RQC group→GO:0006515 is acceptable (broad umbrella over the review's GO:0045947/GO:0072344).
- Evidence alignment: PN dossier lists no reference titles for EIF4E2; alignment is via projected terms. Review's RQC PMIDs (32726578, 35878012, 22751931, 33053355) cover the same repression/RQC biology the GO:0006515 node encodes. No PMID divergence; the only conflict is term-level (GO:0016281).
- Verdict: Biology consistent; one node-level contradiction (PN GO:0016281 vs review REMOVE). RQC story already captured more precisely. Recommended edits: [MAP] flag the EIF4E2 "eIF4F complex" type→GO:0016281 projection as inappropriate (4EHP cannot bind eIF4G / is not an eIF4F component — see review REMOVE of GO:0016281); do not propagate GO:0016281 to O60573.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-07c
- review_yaml: genes/human/EIF4E2/EIF4E2-ai-review.yaml
- PN workbook rows: 2
PN row 1: Translation | Cytosolic translation | Translation initiation | eIF4F complex
- UniProt: O60573
- In branches: TR
- PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Translation initiation|eIF4F complex
status=mapped scope=ok_for_propagation_to_go GO=[GO:0016281 eukaryotic translation initiation factor 4F complex]
rationale: This PN type denotes eIF4F complex components. The GO eukaryotic translation initiation factor 4F complex term resolves the previous deferred state.
- [group] Translation|Cytosolic translation|Translation initiation
status=mapped scope=ok_for_propagation_to_go GO=[GO:0006413 translational initiation]
rationale: This PN group denotes cytosolic translation initiation factors and complexes. Translational initiation is the shared process target.
- [class] Translation|Cytosolic translation
status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.
PN row 2: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes
- UniProt: O60573
- In branches: TR
- PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes
status=no_mapping scope= GO=[]
rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [group] Translation|Cytosolic translation|Ribosome-associated QC
status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
- [class] Translation|Cytosolic translation
status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.
Projected GO annotations (3)
- GO:0006413 translational initiation | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Translation initiation
- GO:0016281 eukaryotic translation initiation factor 4F complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Translation initiation|eIF4F complex
- GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
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.
2026-09-21: focused eIF4F report incorporated; older categorical statements superseded
The earlier statements that EIF4E2 cannot form a productive eIF4F complex or cannot associate with any eIF4G paralog are too broad. PMID:26854219 full-text Results and Fig2C/S2D report endogenous human EIF4E2/eIF4A/eIF4G3 pull-downs, with eIF4G3 depletion impairing hypoxic translation and polysome recruitment. PMID:22678294 explicitly reports eIF4A recruitment. These primary observations support the retained GO:0016281 complex annotation and hypoxic initiation function alongside GIGYF-mediated repression; no new ribosome-binding claim is inferred from polysome association.
Read the entire eif4f-complex-under-hypoxia/openscientist.md report and its plot provenance JSON. It supports context-dependent initiation and repression but incorrectly treats complex composition as untested. Lack of a separately curated Complex Portal entry or experimental GO row is not a negative assay. PMID:28698298 analyzes GIGYF/4E-BP interfaces and cites earlier work for lack of eIF4G interaction; it does not test hypoxic EIF4G3 complex assembly. Its dorsal partner-binding surface lies opposite the cap pocket, contrary to the report's conflation of cap-stacking Trp/Tyr with a proposed dorsal binding defect. Binary binding and complex membership are separate questions.
Delivered plot code hard-codes claimed alignment identities and labels IBA/ISS 'weak'; it supplies no reproducible alignment supporting those numerical claims. They are not adopted as independently verified sequence results. The report is marked DISPUTED, while its supported dual-function findings are incorporated. The complex annotation stays ACCEPT; no new broad or redundant process annotation is added.