EIF5A

UniProt ID: P63241
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0006414 translational elongation
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Strongly supported by UniProt function and experimental work across eukaryotes; this is the central biological process of eIF5A.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid
GO:0003746 translation elongation factor activity
IBA
GO_REF:0000033 		ACCEPT
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.
Reason: Well established across eukaryotes and supported by UniProt; this is eIF5A's defining molecular activity (hypusine-dependent).
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Binds between the exit (E) and
GO:0003723 RNA binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
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.
Reason: RNA binding is documented but generic; the informative function is ribosome binding / elongation factor activity. Retained as a real but non-core capability.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
MRNA-BINDING
GO:0003746 translation elongation factor activity
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic transfer of the elongation factor activity, redundant with and consistent with the IBA/ISS annotations for the same function.
Reason: Correct molecular function, corroborated by stronger IBA and experimental evidence for eIF5A as an elongation factor.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Binds between the exit (E) and
GO:0005634 nucleus
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Electronic (SubCell) nuclear localization, consistent with the experimentally documented hypusine/XPO4-dependent nuclear pool of eIF5A.
Reason: A genuine but minor shuttling pool; the predominant site of action is the cytoplasmic ribosome. Retained as non-core nuclear localization.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Nuclear export of hypusinated protein is mediated by
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic (SubCell) cytoplasmic localization, the predominant compartment where eIF5A acts on translating ribosomes.
Reason: Cytoplasm is eIF5A's primary site of action; corroborated by multiple experimental (EXP/IDA) annotations.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
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.
Reason: Supported by a single early study (peripheral, cytoplasmic side); consistent with ribosome association at the ER but peripheral to the core cytosolic function.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Endoplasmic reticulum membrane
GO:0006414 translational elongation
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic transfer of the elongation BP, redundant with the IBA/IMP annotations for the same process.
Reason: Correct biological process; corroborated by stronger evidence.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
promotes translation elongation and
GO:0043022 ribosome binding
IEA
GO_REF:0000002 		ACCEPT
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.
Reason: Experimentally validated 80S ribosome binding; central to and supporting the elongation factor mechanism.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Binds to 80S ribosomes
PMID:27115996
Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:25416956 UniProtKB:O43186
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: HuRI binary interactome screen capturing eIF5A interactions (including SDCBP/syntenin and DHPS among many homeodomain TFs). Bare protein binding is uninformative.
Reason: Real binary interactions but uninformative term; the biologically meaningful partners (DHPS, SDCBP) are captured elsewhere. Not core.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:O00560
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MODIFY
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.
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 replacements: enzyme binding
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q9BU89
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: HPA immunofluorescence places a pool of eIF5A in the nucleoplasm, consistent with the documented hypusine/XPO4-dependent shuttling pool.
Reason: Genuine nuclear pool but peripheral to the cytoplasmic ribosome-associated core function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: HPA immunofluorescence cytosolic localization, agreeing with eIF5A's predominant cytosolic ribosome-associated site of action.
Reason: Direct evidence for cytosolic localization, consistent with the core function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000314 IDA
GO:0005634 nucleus
EXP
PMID:10944119
Exportin 4: a mediator of a novel nuclear export pathway in ... 		KEEP AS NON CORE
Summary: Experimental nuclear localization linked to XPO4/Ran-mediated nuclear export of hypusinated eIF5A.
Reason: Genuine shuttling pool; non-core relative to cytoplasmic ribosome function.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Nuclear export of hypusinated protein is mediated by
GO:0005634 nucleus
EXP
PMID:19379712
The effect of hypusine modification on the intracellular loc... 		KEEP AS NON CORE
Summary: Experimental nuclear localization shown to depend on hypusine/acetylation status of eIF5A.
Reason: Real but PTM-dependent shuttling pool; non-core.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Hypusine modification promotes the
GO:0005634 nucleus
EXP
PMID:27306458
Structure of the exportin Xpo4 in complex with RanGTP and th... 		KEEP AS NON CORE
Summary: Structural/biochemical study of XPO4-RanGTP-eIF5A export complex; nuclear annotation reflects the shuttling pool.
Reason: Nuclear localization is part of XPO4-mediated shuttling; non-core relative to cytoplasmic translation.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Nuclear export of hypusinated protein is mediated by
GO:0005634 nucleus
EXP
PMID:8253832
Eukaryotic initiation factor 5A is a cellular target of the ... 		KEEP AS NON CORE
Summary: Nuclear localization in the context of eIF5A serving as an HIV-1 Rev cofactor for retroviral mRNA export.
Reason: Nuclear pool tied to the Rev/Rex viral-cofactor context; non-core relative to translation elongation.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
essential for mRNA export of retroviral transcripts
GO:0005737 cytoplasm
EXP
PMID:10944119
Exportin 4: a mediator of a novel nuclear export pathway in ... 		ACCEPT
Summary: Experimental cytoplasmic localization, the predominant compartment for eIF5A.
Reason: Cytoplasm is the core site of action; experimentally supported.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
EXP
PMID:19379712
The effect of hypusine modification on the intracellular loc... 		ACCEPT
Summary: Experimental cytoplasmic localization; hypusination promotes the cytoplasmic pool.
Reason: Consistent with the predominant cytoplasmic site of action.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Hypusine modification promotes the
GO:0005737 cytoplasm
EXP
PMID:27306458
Structure of the exportin Xpo4 in complex with RanGTP and th... 		ACCEPT
Summary: Cytoplasmic localization consistent with eIF5A's ribosome-associated function.
Reason: Core compartment, experimentally supported.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005737 cytoplasm
EXP
PMID:8660923
The subcellular distribution of eukaryotic translation initi... 		ACCEPT
Summary: Early cell-fractionation study documenting cytoplasmic distribution of eIF5A.
Reason: Core compartment, experimentally supported.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:8660923
The subcellular distribution of eukaryotic translation initi... 		KEEP AS NON CORE
Summary: Same fractionation study detecting eIF5A as a peripheral protein on the cytoplasmic face of the ER membrane.
Reason: Peripheral membrane association (cytoplasmic side), consistent with ER-associated ribosomes; peripheral to the core function.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Endoplasmic reticulum membrane
GO:0006414 translational elongation
IMP
PMID:29712776
eIF5A is required for autophagy by mediating ATG3 translatio... 		ACCEPT
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.
Reason: IMP evidence that eIF5A mediates ATG3 translation directly supports its role in translational elongation.
Supporting Evidence:
PMID:29712776
eIF5A is required for autophagy by mediating ATG3 translation.
file:human/EIF5A/EIF5A-uniprot.txt
is required for autophagy by assisting the ribosome in translating the ATG3 protein
GO:0033209 tumor necrosis factor-mediated signaling pathway
IDA
PMID:17187778
Eukaryotic translation initiation factor 5A induces apoptosi... 		KEEP AS NON CORE
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.
Reason: A genuine but pleiotropic stress/apoptosis-context role distinct from the core elongation function.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Also regulates TNF-mediated apoptosis
GO:0045944 positive regulation of transcription by RNA polymerase II
IMP
PMID:15371445
A novel eIF5A complex functions as a regulator of p53 and p5... 		MARK AS OVER ANNOTATED
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.
Reason: eIF5A is a translation factor, not a transcriptional regulator; the transcription effect here is indirect (via p53). Over-annotation of an indirect outcome.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
functions as a regulator of p53 and p53-dependent apoptosis
GO:0098586 cellular response to virus
IMP
PMID:8596953
Inhibition of HIV-1 replication in lymphocytes by mutants of... 		KEEP AS NON CORE
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.
Reason: A genuine microbial-infection cofactor role (Rev/Rex), but distinct from and non-core relative to translation elongation.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Cellular cofactor of human T-cell
GO:0098586 cellular response to virus
IMP
PMID:9465063
Interaction of the HIV-1 rev cofactor eukaryotic initiation ... 		KEEP AS NON CORE
Summary: eIF5A interaction with ribosomal protein L5 in the HIV-1 Rev cofactor context; same viral-cofactor role.
Reason: Genuine Rev-cofactor / viral mRNA export role; non-core relative to translation.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
essential for mRNA export of retroviral transcripts
GO:1902255 positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator
IDA
PMID:15371445
A novel eIF5A complex functions as a regulator of p53 and p5... 		KEEP AS NON CORE
Summary: eIF5A, with SDCBP/syntenin, positively regulates p53-dependent apoptosis. A genuine context-dependent role, downstream of its translation function.
Reason: Real but pleiotropic apoptosis-regulatory role; non-core relative to the elongation function.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
functions as a regulator of p53 and p53-dependent apoptosis
GO:0005829 cytosol
TAS
Reactome:R-HSA-204617 		ACCEPT
Summary: Reactome curated cytosolic localization (hypusine synthesis pathway), consistent with the core compartment.
Reason: Correct cytosolic localization, agrees with experimental evidence.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204617
GO:0005829 cytosol
TAS
Reactome:R-HSA-204647 		ACCEPT
Summary: Reactome curated cytosolic localization, redundant with the other cytosol annotations.
Reason: Correct cytosolic localization.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204647
GO:0005829 cytosol
TAS
Reactome:R-HSA-204662 		ACCEPT
Summary: Reactome curated cytosolic localization, redundant with the other cytosol annotations.
Reason: Correct cytosolic localization.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005829 cytosol cellular_component ECO:0000304 TAS Reactome:R-HSA-204662
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
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.
Reason: Generic "membrane" from a high-throughput proteomics survey; uninformative and not a meaningful compartment assignment for a cytosolic translation factor.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0016020 membrane cellular_component ECO:0007005 HDA PMID:19946888
GO:0003723 RNA binding
HDA
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on ... 		KEEP AS NON CORE
Summary: eIF5A captured in an mRNA-interactome (RNA interactome capture) dataset, consistent with its RNA/mRNA-binding OB-fold and ribosome association.
Reason: Real RNA-binding capability but generic; the informative function is ribosome binding / elongation factor activity.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0003723 RNA binding molecular_function ECO:0007005 HDA PMID:22681889
GO:0003746 translation elongation factor activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity transfer of elongation factor activity from yeast eIF5A, consistent with the IBA/IEA annotations for the same core function.
Reason: Correct core molecular function, supported by orthology and experimental data.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0003746 translation elongation factor activity molecular_function ECO:0000250 ISS
GO:0045901 positive regulation of translational elongation
ISS
GO_REF:0000024 		ACCEPT
Summary: eIF5A positively regulates elongation, especially through stalling motifs. Captures the directionality of its core role.
Reason: Consistent with eIF5A's documented elongation-promoting activity at polyproline and other difficult motifs.
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
specifically required for efficient translation of
GO:0017070 U6 snRNA binding
IDA
PMID:9285100
Interaction of eukaryotic initiation factor 5A with the huma... 		KEEP AS NON CORE
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.
Reason: Single in vitro RNA-binding observation; a real but peripheral activity, not part of the core elongation role.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0017070 U6 snRNA binding molecular_function ECO:0000314 IDA PMID:9285100
GO:0005515 protein binding
IPI
PMID:10381392
Nuclear pore localization and nucleocytoplasmic transport of... 		KEEP AS NON CORE
Summary: Interaction with the export receptor CRM1 in the context of nucleocytoplasmic shuttling of eIF5A. Bare protein binding is uninformative.
Reason: Records a real interaction tied to nuclear export, but the term is uninformative; not part of the core elongation function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:10381392 UniProtKB:Q9PW90
GO:0005515 protein binding
IPI
PMID:10944119
Exportin 4: a mediator of a novel nuclear export pathway in ... 		KEEP AS NON CORE
Summary: Interaction with the XPO4/RanGTP export machinery. The biologically meaningful relationship is eIF5A's export by XPO4; the bare term is uninformative.
Reason: Real interaction underlying nuclear export, but uninformative term; non-core.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:10944119 UniProtKB:Q9C0E2
GO:0005515 protein binding
IPI
PMID:15371445
A novel eIF5A complex functions as a regulator of p53 and p5... 		KEEP AS NON CORE
Summary: Interaction with SDCBP/syntenin in the p53 apoptosis-regulation study. Bare protein binding is uninformative.
Reason: Records a real interaction (SDCBP) but uninformative term; the functional context (p53/apoptosis) is captured in the BP annotations.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:15371445 UniProtKB:O00560
GO:0005515 protein binding
IPI
PMID:17213197
Specificity of the deoxyhypusine hydroxylase-eukaryotic tran... 		MODIFY
Summary: Interaction with DOHH (deoxyhypusine hydroxylase), the enzyme that completes hypusine synthesis on eIF5A. Biologically meaningful enzyme-substrate binding.
Reason: Bare protein binding is uninformative. The partner is the hypusination enzyme DOHH acting on eIF5A; enzyme binding is the appropriate specific term.
Proposed replacements: enzyme binding
Supporting Evidence:
file:human/EIF5A/EIF5A-uniprot.txt
Interacts with DOHH
GO:0005515 protein binding
IPI
PMID:9442029
Identification of the eukaryotic initiation factor 5A as a r... 		KEEP AS NON CORE
Summary: Interaction with tissue transglutaminase II reported as a retinoic-acid-stimulated binding partner. Isolated interaction; bare term is uninformative.
Reason: Records a real but isolated interaction unrelated to the core function; uninformative term.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:9442029 UniProtKB:P21980
GO:0005515 protein binding
IPI
PMID:9465063
Interaction of the HIV-1 rev cofactor eukaryotic initiation ... 		KEEP AS NON CORE
Summary: Interaction with ribosomal protein L5 in the HIV-1 Rev cofactor context. Bare protein binding is uninformative.
Reason: Real interaction tied to the viral-cofactor/ribosome context, but uninformative term; non-core.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:9465063 UniProtKB:P46777
GO:0005634 nucleus
IDA
PMID:12210765
Subcellular localization of the hypusine-containing eukaryot... 		KEEP AS NON CORE
Summary: Immunofluorescence/GFP localization showing a nuclear pool of hypusine-containing eIF5A.
Reason: Genuine nuclear pool; non-core relative to the cytoplasmic ribosome function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005634 nucleus cellular_component ECO:0000314 IDA PMID:12210765
GO:0005642 annulate lamellae
IDA
PMID:12210765
Subcellular localization of the hypusine-containing eukaryot... 		KEEP AS NON CORE
Summary: eIF5A detected at annulate lamellae (stacked nuclear-pore-containing ER membranes), consistent with its nuclear-pore/shuttling association.
Reason: A specialized localization tied to nuclear pore/shuttling; peripheral to the core function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005642 annulate lamellae cellular_component ECO:0000314 IDA
GO:0005643 nuclear pore
IDA
PMID:10381392
Nuclear pore localization and nucleocytoplasmic transport of... 		KEEP AS NON CORE
Summary: eIF5A localized to the nuclear pore, consistent with its CRM1/XPO4-mediated nucleocytoplasmic transport.
Reason: Reflects transport through the nuclear pore; peripheral to the core cytoplasmic function. The part_of qualifier is questionable but the localization is real.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005643 nuclear pore cellular_component ECO:0000314 IDA PMID:10381392
GO:0005737 cytoplasm
IDA
PMID:12210765
Subcellular localization of the hypusine-containing eukaryot... 		ACCEPT
Summary: Direct immunofluorescence/GFP evidence for cytoplasmic localization, the predominant compartment.
Reason: Core compartment, directly supported.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:12210765
GO:0003723 RNA binding
IDA
PMID:15303967
Identification of mRNA that binds to eukaryotic initiation f... 		KEEP AS NON CORE
Summary: Direct evidence that eIF5A binds specific mRNAs (affinity co-purification). A real RNA-binding activity supporting its ribosome-associated function.
Reason: Genuine mRNA binding but generic; the informative function is ribosome binding / elongation factor activity.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0003723 RNA binding molecular_function ECO:0000314 IDA PMID:15303967
GO:0005515 protein binding
IPI
PMID:14622290
Identification and characterization of eukaryotic initiation... 		KEEP AS NON CORE
Summary: Interaction reported during characterization of the paralog eIF5A-2. Bare protein binding is uninformative.
Reason: Records an interaction but uninformative term; not part of the core function.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:14622290 UniProtKB:P49366
GO:0005634 nucleus
IDA
PMID:17187778
Eukaryotic translation initiation factor 5A induces apoptosi... 		KEEP AS NON CORE
Summary: eIF5A nuclear accumulation in response to TNF-alpha (apoptosis context).
Reason: Stimulus-dependent nuclear pool; non-core relative to cytoplasmic translation.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005634 nucleus cellular_component ECO:0000314 IDA PMID:17187778
GO:0005737 cytoplasm
IDA
PMID:17187778
Eukaryotic translation initiation factor 5A induces apoptosi... 		ACCEPT
Summary: Cytoplasmic localization of eIF5A (baseline) in the same TNF-alpha study.
Reason: Core compartment, directly supported.
Supporting Evidence:
file:human/EIF5A/EIF5A-goa.tsv
GO:0005737 cytoplasm cellular_component ECO:0000314 IDA PMID:17187778

Core Functions

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:
translation elongation factor activity
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/EIF5A/EIF5A-uniprot.txt
    Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid
  • file:human/EIF5A/EIF5A-uniprot.txt
    specifically required for efficient translation of

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:
ribosome binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/EIF5A/EIF5A-uniprot.txt
    Binds to 80S ribosomes
  • PMID:27115996
    Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms.
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
GO_REF:0000033
Annotation inferences using phylogenetic trees.
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping.
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data.
PMID:10381392
Nuclear pore localization and nucleocytoplasmic transport of eIF-5A: evidence for direct interaction with the export receptor CRM1.
  • eIF5A interacts with the export receptor CRM1 and localizes to the nuclear pore during nucleocytoplasmic transport.
PMID:10944119
Exportin 4: a mediator of a novel nuclear export pathway in higher eukaryotes.
  • Exportin 4 (XPO4) mediates RanGTP-dependent nuclear export of eIF5A.
PMID:12210765
Subcellular localization of the hypusine-containing eukaryotic initiation factor 5A by immunofluorescent staining and green fluorescent protein tagging.
  • eIF5A localizes predominantly to the cytoplasm with pools at the nucleus and annulate lamellae.
PMID:14622290
Identification and characterization of eukaryotic initiation factor 5A-2.
PMID:15303967
Identification of mRNA that binds to eukaryotic initiation factor 5A by affinity co-purification and differential display.
  • eIF5A binds specific mRNAs identified by affinity co-purification.
PMID:15371445
A novel eIF5A complex functions as a regulator of p53 and p53-dependent apoptosis.
  • eIF5A, with SDCBP/syntenin, regulates p53 and p53-dependent apoptosis.
PMID:17187778
Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor alpha signalling.
  • eIF5A induces apoptosis in colon cancer cells and accumulates in the nucleus in response to TNF-alpha.
PMID:17213197
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.
  • eIF5A interacts with the hypusination enzyme deoxyhypusine hydroxylase (DOHH).
PMID:19379712
The effect of hypusine modification on the intracellular localization of eIF5A.
  • Hypusine modification (and acetylation) regulate the nuclear/cytoplasmic distribution of eIF5A.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:27115996
Evidence for a Negative Cooperativity between eIF5A and eEF2 on Binding to the Ribosome.
  • eIF5A and eEF2 bind translating ribosomes in a mutually exclusive (negatively cooperative) manner.
PMID:27306458
Structure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A.
  • Structural basis for XPO4-RanGTP-mediated nuclear export of hypusinated eIF5A.
PMID:29712776
eIF5A is required for autophagy by mediating ATG3 translation.
  • eIF5A is required for autophagy by mediating efficient translation of ATG3, facilitating LC3B lipidation.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33547280
Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.
  • Loss-of-function eIF5A variants cause Faundes-Banka syndrome; variants reduce ribosome binding, hypusination, and polyproline translation, partially rescued by spermidine.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:8253832
Eukaryotic initiation factor 5A is a cellular target of the human immunodeficiency virus type 1 Rev activation domain mediating trans-activation.
  • eIF5A is a cellular cofactor of HIV-1 Rev required for retroviral mRNA export.
PMID:8596953
Inhibition of HIV-1 replication in lymphocytes by mutants of the Rev cofactor eIF-5A.
  • Mutant eIF5A inhibits HIV-1 replication, consistent with eIF5A acting as a Rev cofactor.
PMID:8660923
The subcellular distribution of eukaryotic translation initiation factor, eIF-5A, in cultured cells.
  • eIF5A is cytoplasmic and peripherally associated with the cytoplasmic face of the ER membrane.
PMID:9285100
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.
  • Hypusine/deoxyhypusine modification is required for eIF5A binding to U6 snRNA and the HIV-1 RRE in vitro.
PMID:9442029
Identification of the eukaryotic initiation factor 5A as a retinoic acid-stimulated cellular binding partner for tissue transglutaminase II.
PMID:9465063
Interaction of the HIV-1 rev cofactor eukaryotic initiation factor 5A with ribosomal protein L5.
  • eIF5A interacts with ribosomal protein L5 in the context of its HIV-1 Rev cofactor function.
Reactome:R-HSA-204617
Hypusine synthesis from eIF5A-lysine (Reactome reaction).
Reactome:R-HSA-204647
Hypusine synthesis from eIF5A-lysine (Reactome reaction).
Reactome:R-HSA-204662
Hypusine synthesis from eIF5A-lysine (Reactome reaction).
file:human/EIF5A/EIF5A-uniprot.txt
UniProt entry P63241 (IF5A1_HUMAN), Eukaryotic translation initiation factor 5A-1.
  • 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.

Suggested Questions for Experts

Q: Beyond polyproline tracts, what is the full sequence/structural repertoire of stalling motifs whose translation depends on hypusinated eIF5A in human cells?

Q: To what extent are eIF5A's apoptosis, p53, and viral-cofactor roles direct versus indirect consequences of its elongation activity on specific mRNAs?

Q: How does the hypusine- and acetylation-dependent nucleocytoplasmic shuttling of eIF5A contribute (if at all) to function beyond regulating its cytoplasmic availability?

Suggested Experiments

Experiment: 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.

Experiment: Cryo-EM of human hypusinated eIF5A on stalled 80S ribosomes at defined motifs to resolve the mechanism of peptidyl-transfer stimulation.

Experiment: Structure-function analysis of FABAS disease variants (e.g., T48N, G106R, E122K) measuring ribosome binding, hypusination efficiency, and polyproline translation, with spermidine rescue.

📚 Additional Documentation

Notes

(EIF5A-notes.md)

EIF5A research notes

UniProt P63241 (IF5A1_HUMAN), 154 aa. HGNC:3300. eIF-5A-1, "eIF-4D", Rev-binding factor.

Core function

Despite the legacy name "initiation factor," eIF5A is a translation elongation/termination factor.
- UniProt FUNCTION: "Translation factor that promotes translation elongation and termination, particularly upon ribosome stalling at specific amino acid sequence contexts PMID:33547280. Binds between the exit (E) and peptidyl (P) site of the ribosome and promotes rescue of stalled ribosome: specifically required for efficient translation of polyproline-containing peptides as well as other motifs that stall the ribosome."
- Acts as a ribosome quality control (RQC) cofactor joining the RQC complex to facilitate peptidyl transfer during CAT-tailing.
- The hypusine modification at Lys-50 is unique to eIF5A proteins and is essential for function [PMID:27306458, PMID:3095320; UniProt PTM]. "eIF-5As are the only known proteins to undergo this modification, which is essential for their function."
- Binds 80S ribosomes; mutually exclusive binding with eEF2 [PMID:27115996 ribosome-binding].

Subcellular location

Cytoplasm + Nucleus + ER membrane (peripheral, cytoplasmic side). Hypusination promotes nuclear export / cytoplasmic localization; nuclear export mediated by XPO4 (exportin 4) with RanGTP [PMID:10944119, PMID:27306458]. Also detected at nuclear pore (IDA PMID:10381392) and annulate lamellae (IDA PMID:12210765) — consistent with XPO4/Ran nuclear-export shuttling.

Moonlighting / pleiotropic roles (mostly downstream consequences of its translation role)

  • Autophagy: required for ATG3 translation (Asp-Asp-Gly motif), facilitating LC3B lipidation PMID:29712776.
  • p53/apoptosis: with syntenin SDCBP regulates p53/TP53 and p53-dependent apoptosis PMID:15371445; positive regulation of intrinsic apoptotic signaling by p53.
  • TNF-mediated apoptosis; nuclear accumulation upon TNFalpha PMID:17187778.
  • Microbial infection cofactor: cellular target of HIV-1 Rev and HTLV-1 Rex, required for retroviral mRNA export PMID:8253832. The two "cellular response to virus" IMP annotations (PMID:8596953, PMID:9465063) reflect this Rev/Rex cofactor role.
  • mRNA decay / NMD: ts mutant accumulates NMD-targeted transcripts PMID:16987817.

Hypusine pathway partners

  • DHPS (deoxyhypusine synthase, P49366) — interaction PMID:10229683; substrate-enzyme complex.
  • DOHH (deoxyhypusine hydroxylase, Q9BU89) — interaction PMID:17213197.
    These two IPI partners (DHPS, DOHH) are the enzymes that install the hypusine modification — biologically meaningful, not generic.

RNA binding

  • IDA RNA binding (PMID:15303967 mRNA binding) and HDA RNA binding (PMID:22681889, RNA interactome capture). U6 snRNA binding IDA (PMID:9285100). eIF5A binds mRNA at the ribosome; OB-fold domain. RNA binding is real but the informative function is ribosome/translation.

Transcription annotation

  • GO:0045944 positive regulation of transcription by RNA Pol II (IMP PMID:15371445) — this paper is about p53 regulation / apoptosis, the transcription effect is indirect (downstream of p53). Non-core.

Interactome IPI partners (high-throughput, mostly homeodomain TFs / generic)

  • PMID:25416956 (Y2H): CRX (O43186), DHPS (P49366), MEOX2 (P50222), REL (Q04864).
  • PMID:32296183 (HuRI binary): MEI4, SDCBP(O00560), GSC2, DHPS, LBX1, REL-2, MEOX2, PICK1. Many homeodomain TFs - likely Y2H artifacts of the OB-fold/basic protein.
  • PMID:33961781 (BioPlex): DOHH (Q9BU89) — meaningful (hypusine pathway).

Disease

Faundes-Banka syndrome (FABAS, autosomal dominant; dev delay, microcephaly, micrognathia). Variants reduce ribosome binding, hypusination, and polyproline translation PMID:33547280.

Curation conclusions

  • CORE MF: translation elongation factor activity (GO:0003746); ribosome binding (GO:0043022) is core/supporting.
  • CORE BP: translational elongation (GO:0006414); positive regulation of translational elongation (GO:0045901).
  • Location cytoplasm/cytosol/nucleus = accept; ER membrane and nuclear pore/annulate lamellae = keep non-core (shuttling/peripheral).
  • p53/TNF/apoptosis/transcription/virus = KEEP_AS_NON_CORE (real but pleiotropic/downstream).
  • Generic protein binding IPI from HT screens = KEEP_AS_NON_CORE or MODIFY for the hypusine-enzyme partners.
  • U6 snRNA binding = single old IDA, peripheral; keep non-core.

Pn Notes

(EIF5A-pn-notes.md)

EIF5A PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P63241
  • 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: 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.
  • Existing/core annotation action counts: ACCEPT: 19; KEEP_AS_NON_CORE: 28; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 2

PN Consistency Summary

  • Consistency: Strong and mutually consistent on the core. Deep research, notes, and review all establish eIF5A as the hypusine-containing elongation/termination factor that binds the 80S ribosome between E and P sites and resolves stalling at polyproline and other difficult motifs. Review ACCEPTs GO:0003746 (elongation factor activity, IBA/IEA/ISS) and GO:0043022 (ribosome binding) as core — matching the PN elongation-type mapping exactly. No contradiction.
  • PN story / NEW pressure: The PN RQC node (GO:0006515, new_to_goa, verified real) is the only place PN asserts a role beyond the review's elongation framing. eIF5A is indeed described (UniProt; notes) as an RQC cofactor joining the RQC complex to facilitate peptidyl transfer/CAT-tailing, so an RQC-process annotation is defensible — but the review does NOT carry any RQC/GO:0006515 term, treating eIF5A purely as an elongation factor. This is a mild NEW pressure: GO:0006515 is plausibly addable but is a broad umbrella, and eIF5A's RQC role is supportive rather than a dedicated surveillance function. Leans already captured / mild over-reach: the elongation-factor activity is the real shared biology; GO:0006515 risks over-stating a QC role for a general elongation factor.
  • Evidence alignment: PN dossier lists no reference titles for EIF5A. Review's core PMIDs (27115996 ribosome binding; 29712776 ATG3/autophagy elongation; 33547280 FABAS disease) all anchor the elongation-factor function the PN elongation node encodes. No divergence.
  • Verdict: Consistent; elongation core fully captured. GO:0006515 RQC umbrella is defensible but mildly over-reaching for a general elongation factor and is absent from the review. Recommended edits: [MAP] treat the EIF5A RQC-group→GO:0006515 projection as low-confidence (eIF5A is an elongation factor with a supportive RQC-cofactor role, not a dedicated surveillance factor); optionally [YAML] consider adding eIF5A's RQC-cofactor role only if curator deems UniProt's CAT-tailing statement annotation-worthy.

Full Consistency Review

  • UniProt: P63241 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Translation elongation|assorted elongation factors AND Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: elongation type=mapped→GO:0003746 (translation elongation factor activity); elongation group=context_only (GO:0006414); RQC group=mapped→GO:0006515; RQC type=no_mapping; class/branch context_only (GO:0002181/GO:0006412 too_broad).
  • Consistency: Strong and mutually consistent on the core. Deep research, notes, and review all establish eIF5A as the hypusine-containing elongation/termination factor that binds the 80S ribosome between E and P sites and resolves stalling at polyproline and other difficult motifs. Review ACCEPTs GO:0003746 (elongation factor activity, IBA/IEA/ISS) and GO:0043022 (ribosome binding) as core — matching the PN elongation-type mapping exactly. No contradiction.
  • PN story / NEW pressure: The PN RQC node (GO:0006515, new_to_goa, verified real) is the only place PN asserts a role beyond the review's elongation framing. eIF5A is indeed described (UniProt; notes) as an RQC cofactor joining the RQC complex to facilitate peptidyl transfer/CAT-tailing, so an RQC-process annotation is defensible — but the review does NOT carry any RQC/GO:0006515 term, treating eIF5A purely as an elongation factor. This is a mild NEW pressure: GO:0006515 is plausibly addable but is a broad umbrella, and eIF5A's RQC role is supportive rather than a dedicated surveillance function. Leans already captured / mild over-reach: the elongation-factor activity is the real shared biology; GO:0006515 risks over-stating a QC role for a general elongation factor.
  • Mapping strategy: Elongation type→GO:0003746 is correct and present in GOA/review. The RQC group→GO:0006515 projection is the borderline call: defensible by UniProt's RQC-cofactor statement, but broad. The group's context_only demotion to GO:0006414 (elongation) is appropriate (the group also houses tRNA synthetases/deacylases). No mapping change required for the elongation node.
  • Evidence alignment: PN dossier lists no reference titles for EIF5A. Review's core PMIDs (27115996 ribosome binding; 29712776 ATG3/autophagy elongation; 33547280 FABAS disease) all anchor the elongation-factor function the PN elongation node encodes. No divergence.
  • Verdict: Consistent; elongation core fully captured. GO:0006515 RQC umbrella is defensible but mildly over-reaching for a general elongation factor and is absent from the review. Recommended edits: [MAP] treat the EIF5A RQC-group→GO:0006515 projection as low-confidence (eIF5A is an elongation factor with a supportive RQC-cofactor role, not a dedicated surveillance factor); optionally [YAML] consider adding eIF5A's RQC-cofactor role only if curator deems UniProt's CAT-tailing statement annotation-worthy.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/EIF5A/EIF5A-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Translation elongation | assorted elongation factors

  • UniProt: P63241
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Translation elongation|assorted elongation factors
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0003746 translation elongation factor activity]
      rationale: This PN type groups cytosolic elongation factors. Translation elongation factor activity is the shared molecular-function target.
    • [group] Translation|Cytosolic translation|Translation elongation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006414 translational elongation]
      rationale: This PN group is an elongation-context bucket, but it also contains tRNA synthetases, tRNA deacylases, and multisynthetase-complex members whose direct shared assertions are narrower molecular functions or complexes. The elongation relationship is retained as context only.
    • [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: P63241
  • 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 (2)

  • GO:0003746 translation elongation factor activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Translation elongation|assorted elongation factors
  • 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.

📄 View Raw YAML

 
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.