id: P63241
gene_symbol: EIF5A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EIF5A (eukaryotic translation initiation factor 5A-1, historically eIF-4D and "Rev-binding factor") is a small, highly conserved translation factor that, despite its legacy "initiation factor" name, acts mainly in translation elongation and termination. It is the only cellular protein to carry hypusine, a unique post-translational modification formed at Lys-50 by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) using spermidine; this modification is essential for its activity. eIF5A binds the 80S ribosome between the exit (E) and peptidyl (P) tRNA sites and stimulates peptide-bond formation at sequences that are intrinsically difficult to translate, most notably consecutive prolines (polyproline tracts) and other stalling motifs, thereby promoting efficient elongation through these contexts and resolving ribosome stalling. eIF5A and eEF2 bind translating ribosomes in a mutually exclusive manner. Through this elongation-promoting activity it supports specific cellular programs, including autophagy (by enabling translation of ATG3) and broad proteome synthesis. eIF5A is predominantly cytoplasmic and ribosome-associated, with a hypusine- and XPO4/RanGTP-dependent nucleocytoplasmic shuttling pool that can localize to the nucleus, nuclear pore and annulate lamellae. Hypusine-dependent localization and abundance changes underlie additional context-dependent roles in apoptosis and stress responses, and eIF5A serves as a cellular cofactor for retroviral (HIV-1 Rev / HTLV-1 Rex) mRNA export. Loss-of-function variants cause the autosomal dominant Faundes-Banka syndrome.
alternative_products:
- name: 1 (B, C, D)
  id: P63241-1
- name: 2 (A)
  id: P63241-2
  sequence_note: VSP_022020
existing_annotations:
- term:
    id: GO:0006414
    label: translational elongation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: eIF5A promotes translation elongation, particularly through ribosome-stalling motifs such as polyproline tracts. This phylogenetically inferred BP annotation captures the gene's core biological role.
    action: ACCEPT
    reason: Strongly supported by UniProt function and experimental work across eukaryotes; this is the central biological process of eIF5A.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid
- term:
    id: GO:0003746
    label: translation elongation factor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: eIF5A acts as a translation elongation factor, binding between the E and P sites of the ribosome to stimulate peptide-bond formation at difficult motifs. This is the core molecular function.
    action: ACCEPT
    reason: Well established across eukaryotes and supported by UniProt; this is eIF5A's defining molecular activity (hypusine-dependent).
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Binds between the exit (E) and
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: eIF5A contains an OB-fold and binds RNA (mRNA, and in vitro U6 snRNA / RRE). RNA binding is real but is a supporting activity subordinate to its ribosome-associated elongation function.
    action: KEEP_AS_NON_CORE
    reason: RNA binding is documented but generic; the informative function is ribosome binding / elongation factor activity. Retained as a real but non-core capability.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: MRNA-BINDING
- term:
    id: GO:0003746
    label: translation elongation factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic transfer of the elongation factor activity, redundant with and consistent with the IBA/ISS annotations for the same function.
    action: ACCEPT
    reason: Correct molecular function, corroborated by stronger IBA and experimental evidence for eIF5A as an elongation factor.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Binds between the exit (E) and
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (SubCell) nuclear localization, consistent with the experimentally documented hypusine/XPO4-dependent nuclear pool of eIF5A.
    action: KEEP_AS_NON_CORE
    reason: A genuine but minor shuttling pool; the predominant site of action is the cytoplasmic ribosome. Retained as non-core nuclear localization.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Nuclear export of hypusinated protein is mediated by
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (SubCell) cytoplasmic localization, the predominant compartment where eIF5A acts on translating ribosomes.
    action: ACCEPT
    reason: Cytoplasm is eIF5A's primary site of action; corroborated by multiple experimental (EXP/IDA) annotations.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: eIF5A was detected as a peripheral protein on the cytoplasmic face of the ER membrane in early fractionation work. This is a peripheral/contextual localization, not its core compartment.
    action: KEEP_AS_NON_CORE
    reason: Supported by a single early study (peripheral, cytoplasmic side); consistent with ribosome association at the ER but peripheral to the core cytosolic function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006414
    label: translational elongation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic transfer of the elongation BP, redundant with the IBA/IMP annotations for the same process.
    action: ACCEPT
    reason: Correct biological process; corroborated by stronger evidence.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: promotes translation elongation and
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: eIF5A binds the 80S ribosome (experimentally demonstrated), inserting between the E and P sites. Ribosome binding is the structural basis for its elongation factor activity.
    action: ACCEPT
    reason: Experimentally validated 80S ribosome binding; central to and supporting the elongation factor mechanism.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Binds to 80S ribosomes
    - reference_id: PMID:27115996
      supporting_text: Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput Y2H interactome screen capturing eIF5A interactions, mostly with homeodomain/bZIP transcription factors (CRX, MEOX2, REL) plus DHPS. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real binary interactions but the term is uninformative and the partners (largely homeodomain TFs) are likely OB-fold/Y2H artifacts; not part of the core elongation function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:O43186
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI binary interactome screen capturing eIF5A interactions (including SDCBP/syntenin and DHPS among many homeodomain TFs). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real binary interactions but uninformative term; the biologically meaningful partners (DHPS, SDCBP) are captured elsewhere. Not core.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O00560
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification capturing the eIF5A-DOHH (Q9BU89) interaction. DOHH is the deoxyhypusine hydroxylase that completes hypusine synthesis, so this interaction is biologically meaningful, though the term itself is uninformative.
    action: MODIFY
    reason: Bare protein binding is uninformative. The WITH partner is DOHH (Q9BU89), an enzyme of the hypusination pathway acting on eIF5A; the specific enzyme-binding relationship is better captured by enzyme binding.
    proposed_replacement_terms:
    - id: GO:0019899
      label: enzyme binding
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9BU89
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence places a pool of eIF5A in the nucleoplasm, consistent with the documented hypusine/XPO4-dependent shuttling pool.
    action: KEEP_AS_NON_CORE
    reason: Genuine nuclear pool but peripheral to the cytoplasmic ribosome-associated core function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence cytosolic localization, agreeing with eIF5A's predominant cytosolic ribosome-associated site of action.
    action: ACCEPT
    reason: Direct evidence for cytosolic localization, consistent with the core function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:10944119
  qualifier: located_in
  review:
    summary: Experimental nuclear localization linked to XPO4/Ran-mediated nuclear export of hypusinated eIF5A.
    action: KEEP_AS_NON_CORE
    reason: Genuine shuttling pool; non-core relative to cytoplasmic ribosome function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Nuclear export of hypusinated protein is mediated by
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:19379712
  qualifier: located_in
  review:
    summary: Experimental nuclear localization shown to depend on hypusine/acetylation status of eIF5A.
    action: KEEP_AS_NON_CORE
    reason: Real but PTM-dependent shuttling pool; non-core.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Hypusine modification promotes the
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:27306458
  qualifier: located_in
  review:
    summary: Structural/biochemical study of XPO4-RanGTP-eIF5A export complex; nuclear annotation reflects the shuttling pool.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is part of XPO4-mediated shuttling; non-core relative to cytoplasmic translation.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Nuclear export of hypusinated protein is mediated by
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:8253832
  qualifier: located_in
  review:
    summary: Nuclear localization in the context of eIF5A serving as an HIV-1 Rev cofactor for retroviral mRNA export.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool tied to the Rev/Rex viral-cofactor context; non-core relative to translation elongation.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: essential for mRNA export of retroviral transcripts
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:10944119
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic localization, the predominant compartment for eIF5A.
    action: ACCEPT
    reason: Cytoplasm is the core site of action; experimentally supported.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:19379712
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic localization; hypusination promotes the cytoplasmic pool.
    action: ACCEPT
    reason: Consistent with the predominant cytoplasmic site of action.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Hypusine modification promotes the
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27306458
  qualifier: located_in
  review:
    summary: Cytoplasmic localization consistent with eIF5A's ribosome-associated function.
    action: ACCEPT
    reason: Core compartment, experimentally supported.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:8660923
  qualifier: located_in
  review:
    summary: Early cell-fractionation study documenting cytoplasmic distribution of eIF5A.
    action: ACCEPT
    reason: Core compartment, experimentally supported.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:8660923
  qualifier: located_in
  review:
    summary: Same fractionation study detecting eIF5A as a peripheral protein on the cytoplasmic face of the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Peripheral membrane association (cytoplasmic side), consistent with ER-associated ribosomes; peripheral to the core function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006414
    label: translational elongation
  evidence_type: IMP
  original_reference_id: PMID:29712776
  qualifier: involved_in
  review:
    summary: eIF5A is required for translation of ATG3 (at a difficult motif), thereby enabling autophagy. This is a specific, experimentally demonstrated example of eIF5A's elongation function.
    action: ACCEPT
    reason: IMP evidence that eIF5A mediates ATG3 translation directly supports its role in translational elongation.
    supported_by:
    - reference_id: PMID:29712776
      supporting_text: eIF5A is required for autophagy by mediating ATG3 translation.
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: is required for autophagy by assisting the ribosome in translating the ATG3 protein
- term:
    id: GO:0033209
    label: tumor necrosis factor-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:17187778
  qualifier: involved_in
  review:
    summary: eIF5A nuclear accumulation and apoptotic effects in response to TNF-alpha signaling. This is a context-dependent downstream role, not the core translation function.
    action: KEEP_AS_NON_CORE
    reason: A genuine but pleiotropic stress/apoptosis-context role distinct from the core elongation function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Also regulates TNF-mediated apoptosis
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:15371445
  qualifier: involved_in
  review:
    summary: Derived from a study where eIF5A (with SDCBP) regulates p53 and p53-dependent apoptosis. The transcriptional effect is an indirect downstream consequence, not a direct eIF5A transcription function.
    action: MARK_AS_OVER_ANNOTATED
    reason: eIF5A is a translation factor, not a transcriptional regulator; the transcription effect here is indirect (via p53). Over-annotation of an indirect outcome.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: functions as a regulator of p53 and p53-dependent apoptosis
- term:
    id: GO:0098586
    label: cellular response to virus
  evidence_type: IMP
  original_reference_id: PMID:8596953
  qualifier: involved_in
  review:
    summary: eIF5A serves as a cellular cofactor for HIV-1 Rev-mediated retroviral mRNA export. The "cellular response to virus" framing reflects this viral-cofactor role.
    action: KEEP_AS_NON_CORE
    reason: A genuine microbial-infection cofactor role (Rev/Rex), but distinct from and non-core relative to translation elongation.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Cellular cofactor of human T-cell
- term:
    id: GO:0098586
    label: cellular response to virus
  evidence_type: IMP
  original_reference_id: PMID:9465063
  qualifier: involved_in
  review:
    summary: eIF5A interaction with ribosomal protein L5 in the HIV-1 Rev cofactor context; same viral-cofactor role.
    action: KEEP_AS_NON_CORE
    reason: Genuine Rev-cofactor / viral mRNA export role; non-core relative to translation.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: essential for mRNA export of retroviral transcripts
- term:
    id: GO:1902255
    label: positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator
  evidence_type: IDA
  original_reference_id: PMID:15371445
  qualifier: involved_in
  review:
    summary: eIF5A, with SDCBP/syntenin, positively regulates p53-dependent apoptosis. A genuine context-dependent role, downstream of its translation function.
    action: KEEP_AS_NON_CORE
    reason: Real but pleiotropic apoptosis-regulatory role; non-core relative to the elongation function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: functions as a regulator of p53 and p53-dependent apoptosis
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204617
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization (hypusine synthesis pathway), consistent with the core compartment.
    action: ACCEPT
    reason: Correct cytosolic localization, agrees with experimental evidence.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204617
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204647
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization, redundant with the other cytosol annotations.
    action: ACCEPT
    reason: Correct cytosolic localization.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204647
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204662
  qualifier: located_in
  review:
    summary: Reactome curated cytosolic localization, redundant with the other cytosol annotations.
    action: ACCEPT
    reason: Correct cytosolic localization.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204662
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: eIF5A appeared in a high-throughput membrane-proteome dataset of NK cells. This is a generic, non-specific localization likely reflecting ribosome/peripheral membrane association.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic "membrane" from a high-throughput proteomics survey; uninformative and not a meaningful compartment assignment for a cytosolic translation factor.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: eIF5A captured in an mRNA-interactome (RNA interactome capture) dataset, consistent with its RNA/mRNA-binding OB-fold and ribosome association.
    action: KEEP_AS_NON_CORE
    reason: Real RNA-binding capability but generic; the informative function is ribosome binding / elongation factor activity.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0003723 RNA binding molecular_function ECO:0007005 HDA PMID:22681889
- term:
    id: GO:0003746
    label: translation elongation factor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer of elongation factor activity from yeast eIF5A, consistent with the IBA/IEA annotations for the same core function.
    action: ACCEPT
    reason: Correct core molecular function, supported by orthology and experimental data.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0003746 translation elongation factor activity molecular_function ECO:0000250 ISS
- term:
    id: GO:0045901
    label: positive regulation of translational elongation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: eIF5A positively regulates elongation, especially through stalling motifs. Captures the directionality of its core role.
    action: ACCEPT
    reason: Consistent with eIF5A's documented elongation-promoting activity at polyproline and other difficult motifs.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: specifically required for efficient translation of
- term:
    id: GO:0017070
    label: U6 snRNA binding
  evidence_type: IDA
  original_reference_id: PMID:9285100
  qualifier: enables
  review:
    summary: eIF5A binds U6 snRNA (and the HIV-1 RRE) in vitro in a hypusine-dependent manner. An isolated in vitro RNA-binding observation, peripheral to its core function.
    action: KEEP_AS_NON_CORE
    reason: Single in vitro RNA-binding observation; a real but peripheral activity, not part of the core elongation role.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0017070 U6 snRNA binding molecular_function ECO:0000314 IDA PMID:9285100
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10381392
  qualifier: enables
  review:
    summary: Interaction with the export receptor CRM1 in the context of nucleocytoplasmic shuttling of eIF5A. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction tied to nuclear export, but the term is uninformative; not part of the core elongation function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:10381392 UniProtKB:Q9PW90
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10944119
  qualifier: enables
  review:
    summary: Interaction with the XPO4/RanGTP export machinery. The biologically meaningful relationship is eIF5A's export by XPO4; the bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction underlying nuclear export, but uninformative term; non-core.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:10944119 UniProtKB:Q9C0E2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15371445
  qualifier: enables
  review:
    summary: Interaction with SDCBP/syntenin in the p53 apoptosis-regulation study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (SDCBP) but uninformative term; the functional context (p53/apoptosis) is captured in the BP annotations.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:15371445 UniProtKB:O00560
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17213197
  qualifier: enables
  review:
    summary: Interaction with DOHH (deoxyhypusine hydroxylase), the enzyme that completes hypusine synthesis on eIF5A. Biologically meaningful enzyme-substrate binding.
    action: MODIFY
    reason: Bare protein binding is uninformative. The partner is the hypusination enzyme DOHH acting on eIF5A; enzyme binding is the appropriate specific term.
    proposed_replacement_terms:
    - id: GO:0019899
      label: enzyme binding
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
      supporting_text: Interacts with DOHH
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9442029
  qualifier: enables
  review:
    summary: Interaction with tissue transglutaminase II reported as a retinoic-acid-stimulated binding partner. Isolated interaction; bare term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real but isolated interaction unrelated to the core function; uninformative term.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:9442029 UniProtKB:P21980
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9465063
  qualifier: enables
  review:
    summary: Interaction with ribosomal protein L5 in the HIV-1 Rev cofactor context. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction tied to the viral-cofactor/ribosome context, but uninformative term; non-core.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:9465063 UniProtKB:P46777
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12210765
  qualifier: located_in
  review:
    summary: Immunofluorescence/GFP localization showing a nuclear pool of hypusine-containing eIF5A.
    action: KEEP_AS_NON_CORE
    reason: Genuine nuclear pool; non-core relative to the cytoplasmic ribosome function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component ECO:0000314 IDA PMID:12210765
- term:
    id: GO:0005642
    label: annulate lamellae
  evidence_type: IDA
  original_reference_id: PMID:12210765
  qualifier: located_in
  review:
    summary: eIF5A detected at annulate lamellae (stacked nuclear-pore-containing ER membranes), consistent with its nuclear-pore/shuttling association.
    action: KEEP_AS_NON_CORE
    reason: A specialized localization tied to nuclear pore/shuttling; peripheral to the core function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005642 annulate lamellae cellular_component ECO:0000314 IDA
- term:
    id: GO:0005643
    label: nuclear pore
  evidence_type: IDA
  original_reference_id: PMID:10381392
  qualifier: part_of
  review:
    summary: eIF5A localized to the nuclear pore, consistent with its CRM1/XPO4-mediated nucleocytoplasmic transport.
    action: KEEP_AS_NON_CORE
    reason: Reflects transport through the nuclear pore; peripheral to the core cytoplasmic function. The part_of qualifier is questionable but the localization is real.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005643 nuclear pore cellular_component ECO:0000314 IDA PMID:10381392
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:12210765
  qualifier: located_in
  review:
    summary: Direct immunofluorescence/GFP evidence for cytoplasmic localization, the predominant compartment.
    action: ACCEPT
    reason: Core compartment, directly supported.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:12210765
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IDA
  original_reference_id: PMID:15303967
  qualifier: enables
  review:
    summary: Direct evidence that eIF5A binds specific mRNAs (affinity co-purification). A real RNA-binding activity supporting its ribosome-associated function.
    action: KEEP_AS_NON_CORE
    reason: Genuine mRNA binding but generic; the informative function is ribosome binding / elongation factor activity.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0003723 RNA binding molecular_function ECO:0000314 IDA PMID:15303967
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14622290
  qualifier: enables
  review:
    summary: Interaction reported during characterization of the paralog eIF5A-2. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records an interaction but uninformative term; not part of the core function.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:14622290 UniProtKB:P49366
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17187778
  qualifier: located_in
  review:
    summary: eIF5A nuclear accumulation in response to TNF-alpha (apoptosis context).
    action: KEEP_AS_NON_CORE
    reason: Stimulus-dependent nuclear pool; non-core relative to cytoplasmic translation.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component ECO:0000314 IDA PMID:17187778
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17187778
  qualifier: located_in
  review:
    summary: Cytoplasmic localization of eIF5A (baseline) in the same TNF-alpha study.
    action: ACCEPT
    reason: Core compartment, directly supported.
    supported_by:
    - reference_id: file:human/EIF5A/EIF5A-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:17187778
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees.
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping.
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data.
  findings: []
- id: PMID:10381392
  title: 'Nuclear pore localization and nucleocytoplasmic transport of eIF-5A: evidence for direct interaction with the export receptor CRM1.'
  findings:
  - statement: eIF5A interacts with the export receptor CRM1 and localizes to the nuclear pore during nucleocytoplasmic transport.
    reference_section_type: RESULTS
- id: PMID:10944119
  title: 'Exportin 4: a mediator of a novel nuclear export pathway in higher eukaryotes.'
  findings:
  - statement: Exportin 4 (XPO4) mediates RanGTP-dependent nuclear export of eIF5A.
    reference_section_type: RESULTS
- id: PMID:12210765
  title: Subcellular localization of the hypusine-containing eukaryotic initiation factor 5A by immunofluorescent staining and green fluorescent protein tagging.
  findings:
  - statement: eIF5A localizes predominantly to the cytoplasm with pools at the nucleus and annulate lamellae.
    reference_section_type: RESULTS
- id: PMID:14622290
  title: Identification and characterization of eukaryotic initiation factor 5A-2.
  findings: []
- id: PMID:15303967
  title: Identification of mRNA that binds to eukaryotic initiation factor 5A by affinity co-purification and differential display.
  findings:
  - statement: eIF5A binds specific mRNAs identified by affinity co-purification.
    reference_section_type: RESULTS
- id: PMID:15371445
  title: A novel eIF5A complex functions as a regulator of p53 and p53-dependent apoptosis.
  findings:
  - statement: eIF5A, with SDCBP/syntenin, regulates p53 and p53-dependent apoptosis.
    reference_section_type: RESULTS
- id: PMID:17187778
  title: Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor alpha signalling.
  findings:
  - statement: eIF5A induces apoptosis in colon cancer cells and accumulates in the nucleus in response to TNF-alpha.
    reference_section_type: RESULTS
- id: PMID:17213197
  title: 'Specificity of the deoxyhypusine hydroxylase-eukaryotic translation initiation factor (eIF5A) interaction: identification of amino acid residues of the enzyme required for binding of its substrate, deoxyhypusine-containing eIF5A.'
  findings:
  - statement: eIF5A interacts with the hypusination enzyme deoxyhypusine hydroxylase (DOHH).
    reference_section_type: RESULTS
- id: PMID:19379712
  title: The effect of hypusine modification on the intracellular localization of eIF5A.
  findings:
  - statement: Hypusine modification (and acetylation) regulate the nuclear/cytoplasmic distribution of eIF5A.
    reference_section_type: RESULTS
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:27115996
  title: Evidence for a Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_27115996.md title matches YAML; supports the core MF (ribosome binding / translation elongation) — eIF5A and eEF2 bind translating ribosomes in a negatively cooperative manner, mechanistically placing eIF5A in elongation."
  findings:
  - statement: eIF5A and eEF2 bind translating ribosomes in a mutually exclusive (negatively cooperative) manner.
    reference_section_type: RESULTS
- id: PMID:27306458
  title: Structure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A.
  findings:
  - statement: Structural basis for XPO4-RanGTP-mediated nuclear export of hypusinated eIF5A.
    reference_section_type: RESULTS
- id: PMID:29712776
  title: eIF5A is required for autophagy by mediating ATG3 translation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_29712776.md title matches YAML; GOA anchors this PMID to GO:0006414 (translational elongation, IMP), directly supporting the core elongation-factor function via efficient (polyproline-containing ATG3) translation."
  findings:
  - statement: eIF5A is required for autophagy by mediating efficient translation of ATG3, facilitating LC3B lipidation.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33547280
  title: Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_33547280.md title matches YAML; in-vivo human genetic evidence — LoF eIF5A variants reduce ribosome binding, hypusination, and polyproline translation, corroborating the core translation-elongation function."
  findings:
  - statement: Loss-of-function eIF5A variants cause Faundes-Banka syndrome; variants reduce ribosome binding, hypusination, and polyproline translation, partially rescued by spermidine.
    reference_section_type: RESULTS
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:8253832
  title: Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation.
  findings:
  - statement: eIF5A is a cellular cofactor of HIV-1 Rev required for retroviral mRNA export.
    reference_section_type: RESULTS
- id: PMID:8596953
  title: Inhibition of HIV-1 replication in lymphocytes by mutants of the Rev cofactor eIF-5A.
  findings:
  - statement: Mutant eIF5A inhibits HIV-1 replication, consistent with eIF5A acting as a Rev cofactor.
    reference_section_type: RESULTS
- id: PMID:8660923
  title: The subcellular distribution of eukaryotic translation initiation factor, eIF-5A, in cultured cells.
  findings:
  - statement: eIF5A is cytoplasmic and peripherally associated with the cytoplasmic face of the ER membrane.
    reference_section_type: RESULTS
- id: PMID:9285100
  title: Interaction of eukaryotic initiation factor 5A with the human immunodeficiency virus type 1 Rev response element RNA and U6 snRNA requires deoxyhypusine or hypusine modification.
  findings:
  - statement: Hypusine/deoxyhypusine modification is required for eIF5A binding to U6 snRNA and the HIV-1 RRE in vitro.
    reference_section_type: RESULTS
- id: PMID:9442029
  title: Identification of the eukaryotic initiation factor 5A as a retinoic acid-stimulated cellular binding partner for tissue transglutaminase II.
  findings: []
- id: PMID:9465063
  title: Interaction of the HIV-1 rev cofactor eukaryotic initiation factor 5A with ribosomal protein L5.
  findings:
  - statement: eIF5A interacts with ribosomal protein L5 in the context of its HIV-1 Rev cofactor function.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-204617
  title: Hypusine synthesis from eIF5A-lysine (Reactome reaction).
  findings: []
- id: Reactome:R-HSA-204647
  title: Hypusine synthesis from eIF5A-lysine (Reactome reaction).
  findings: []
- id: Reactome:R-HSA-204662
  title: Hypusine synthesis from eIF5A-lysine (Reactome reaction).
  findings: []
- id: file:human/EIF5A/EIF5A-uniprot.txt
  title: UniProt entry P63241 (IF5A1_HUMAN), Eukaryotic translation initiation factor 5A-1.
  findings:
  - statement: Translation factor that promotes translation elongation and termination, binding between the E and P sites of the ribosome and required for efficient translation of polyproline and other stalling motifs; carries the essential hypusine modification at Lys-50; predominantly cytoplasmic with XPO4-mediated nuclear shuttling.
    reference_section_type: OTHER
core_functions:
- description: Hypusine-dependent translation elongation factor that binds the 80S ribosome between the E and P sites and stimulates peptide-bond formation at intrinsically difficult sequences (polyproline tracts and other stalling motifs), promoting efficient elongation and termination and resolving ribosome stalling.
  molecular_function:
    id: GO:0003746
    label: translation elongation factor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
    supporting_text: Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid
  - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
    supporting_text: specifically required for efficient translation of
- description: Ribosome binding underlying its elongation activity; eIF5A binds 80S ribosomes and competes with eEF2, inserting between the E and P sites at the peptidyl transferase center.
  molecular_function:
    id: GO:0043022
    label: ribosome binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/EIF5A/EIF5A-uniprot.txt
    supporting_text: Binds to 80S ribosomes
  - reference_id: PMID:27115996
    supporting_text: Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.
proposed_new_terms: []
suggested_questions:
- question: Beyond polyproline tracts, what is the full sequence/structural repertoire of stalling motifs whose translation depends on hypusinated eIF5A in human cells?
- question: To what extent are eIF5A's apoptosis, p53, and viral-cofactor roles direct versus indirect consequences of its elongation activity on specific mRNAs?
- question: How does the hypusine- and acetylation-dependent nucleocytoplasmic shuttling of eIF5A contribute (if at all) to function beyond regulating its cytoplasmic availability?
suggested_experiments:
- description: Ribosome profiling in eIF5A-depleted or hypusination-deficient (DHPS/DOHH-inhibited) human cells to map genome-wide stalling sites and the dependency of specific transcripts (e.g., ATG3) on eIF5A.
- description: Cryo-EM of human hypusinated eIF5A on stalled 80S ribosomes at defined motifs to resolve the mechanism of peptidyl-transfer stimulation.
- description: Structure-function analysis of FABAS disease variants (e.g., T48N, G106R, E122K) measuring ribosome binding, hypusination efficiency, and polyproline translation, with spermidine rescue.