NEMF

UniProt ID: O60524
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

NEMF (Nuclear Export Mediator Factor; also called RQC2, the mammalian ortholog of yeast Rqc2/Tae2 and bacterial RqcH) is a core subunit of the ribosome-associated quality control (RQC) complex that acts on stalled 60S large ribosomal subunits. After an aberrant ribosome stalls and is split, NEMF recognizes the exposed nascent-chain-conjugated (peptidyl) tRNA in the 60S subunit, which allows it to discriminate occupied from empty 60S, and it recruits and stabilizes the E3 ubiquitin ligase LTN1/Listerin. NEMF additionally catalyzes CAT tailing, in which (in an mRNA- and 40S-independent manner) it delivers mainly alanine-charged tRNA (and other aminoacyl-tRNAs) to the ribosomal A site and directs non-templated C-terminal elongation of the stalled nascent chain, generating C-terminal alanine/threonine (CAT) tails. These tails promote degradation of the stalled chain by two routes. In the canonical RQC-L pathway they expose buried lysines for LTN1-dependent ubiquitination, and in the alternative RQC-C pathway they form a C-terminal alanine degron recognized by C-end-rule E3 ligases (CRL2-KLHDC10 and RCHY1/PIRH2). NEMF acts in the cytosol on cytosolic ribosomes; loss of NEMF function causes accumulation of toxic, aggregation-prone nascent chains, and biallelic NEMF variants cause an autosomal-recessive neurodevelopmental disorder with peripheral neuropathy.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0000049 tRNA binding
IBA
GO_REF:0000033 		ACCEPT
Summary: NEMF binds tRNA - both the nascent-chain-conjugated peptidyl-tRNA it uses to sense stalled 60S and the aminoacyl-tRNA it delivers for CAT tailing. tRNA binding is conserved across the NEMF/Rqc2 family.
Reason: Well supported; the more specific alpha-aminoacyl-tRNA binding (GO:1904678) is also annotated. tRNA binding is integral to NEMF's 60S sensing and CAT-tailing activities.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF specifically binds stalled 60S ribosomal subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety
GO:0043023 ribosomal large subunit binding
IBA
GO_REF:0000033 		ACCEPT
Summary: NEMF binds the stalled 60S large ribosomal subunit, making multiple contacts with 60S and the P-site tRNA. This is core to its RQC function.
Reason: Directly demonstrated structurally and biochemically; binding 60S is the basis for NEMF's nascent-chain sensing.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF specifically binds stalled 60S ribosomal subunits
GO:1990112 RQC complex
IBA
GO_REF:0000033 		ACCEPT
Summary: NEMF is one of the three defining subunits of the RQC complex (LTN1, TCF25, NEMF) on the 60S subunit.
Reason: Directly demonstrated; conserved RQC complex membership.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
GO:0072344 rescue of stalled cytosolic ribosome
IBA
GO_REF:0000033 		ACCEPT
Summary: NEMF participates in resolving stalled ribosomes by sensing 60S-nascent chain complexes and triggering downstream degradation/CAT-tailing.
Reason: Conserved and experimentally supported RQC role.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
frees 60S subunit ribosomes from the stalled translation complex
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: By recruiting LTN1 and CAT-tailing nascent chains to promote their ubiquitination, NEMF is integral to ribosome-associated ubiquitin-dependent degradation.
Reason: Conserved and experimentally supported; NEMF promotes degradation of stalled nascent chains.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
as well as their ubiquitin-mediated proteasomal degradation
GO:0005634 nucleus
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Nuclear localization derives from the legacy nuclear-export-mediator-factor role (PubMed:16103875), predating NEMF's characterization as an RQC factor. The predominant, well-supported localization is cytosolic.
Reason: UniProt lists Nucleus by ECO:0000305 based on the older nuclear-export role, but the core, extensively documented function of NEMF is cytoplasmic RQC; nuclear localization is peripheral.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF may also indirectly play a role in nuclear export
GO:0005829 cytosol
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of cytosolic localization, consistent with the experimentally documented site of NEMF action.
Reason: Correct compartment; redundant with IDA cytosol evidence.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0140708 CAT tailing
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic (ARBA, ortholog) assignment of CAT tailing, the signature catalytic activity of NEMF, consistent with direct experimental IDA evidence.
Reason: Correct core process; NEMF is the mammalian enzyme that adds C-terminal alanine (CAT) tails to stalled nascent chains.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment of the RQC ubiquitin-dependent catabolic process, consistent with experimental evidence.
Reason: Correct core process; redundant with IDA evidence.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
as well as their ubiquitin-mediated proteasomal degradation
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948318 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948360 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948362 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948427 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948458 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9954723 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9954727 		ACCEPT
Summary: Reactome curation of NEMF cytosolic localization.
Reason: Correct compartment; redundant with experimental cytosol annotations.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0072344 rescue of stalled cytosolic ribosome
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of NEMF's RQC rescue role.
Reason: Consistent with experimentally supported RQC function.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:1990112 RQC complex
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of NEMF as an RQC complex subunit.
Reason: Consistent with experimentally demonstrated RQC complex membership.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of NEMF's RQC catabolic role.
Reason: Consistent with the experimentally supported process.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:0022626 cytosolic ribosome
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: NEMF acts on the cytosolic 60S ribosome; the cryo-EM RQC structure places NEMF on the 60S subunit contacting the P-site tRNA.
Reason: Directly demonstrated; NEMF functions while bound to the cytosolic ribosome.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF specifically binds stalled 60S ribosomal subunits
GO:0022626 cytosolic ribosome
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: NEMF acts on the cytosolic ribosome during alanine tailing of stalled nascent chains.
Reason: Directly demonstrated; NEMF's Ala-tailing activity occurs on 60S-nascent chain complexes.
Supporting Evidence:
PMID:33909987
mediated by tRNA-Ala binding and Ala tailing
GO:0043023 ribosomal large subunit binding
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: Direct evidence that NEMF binds the 60S large subunit, making simultaneous contacts with 60S and the peptidyl-tRNA.
Reason: Core; experimentally demonstrated 60S binding underlies NEMF's nascent-chain sensing.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF specifically binds stalled 60S ribosomal subunits
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: Direct experimental evidence for NEMF's role in resolving stalled 60S-nascent chain complexes within RQC.
Reason: Core, experimentally supported RQC/rescue function.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
frees 60S subunit ribosomes from the stalled translation complex
GO:0140708 CAT tailing
IDA
PMID:33406423
Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Mor... 		ACCEPT
Summary: Direct evidence that mammalian NEMF modifies stalled (nonstop) translation products with non-templated C-terminal alanine-rich (CAT) tails. This is NEMF's signature catalytic activity.
Reason: Core molecular activity demonstrated directly in mammalian cells; NEMF is the CAT- tailing enzyme.
Supporting Evidence:
PMID:33406423
NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids
GO:0140708 CAT tailing
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: Direct evidence that NEMF performs alanine tailing of stalled nascent chains via tRNA-Ala binding, in both Listerin-dependent and Listerin-independent routes.
Reason: Core; experimentally demonstrated CAT/Ala tailing activity.
Supporting Evidence:
PMID:33909987
mammalian NEMF has an additional, Listerin-independent proteolytic role, which, as in bacteria, is mediated by tRNA-Ala binding and Ala tailing
GO:1904678 alpha-aminoacyl-tRNA binding
IDA
PMID:33406423
Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Mor... 		ACCEPT
Summary: NEMF binds aminoacyl-tRNA (mainly Ala-charged) to deliver it to the A site during CAT tailing. This is the molecular function underlying its tailing activity.
Reason: Core molecular function; directly supports the CAT-tailing mechanism.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site
GO:1904678 alpha-aminoacyl-tRNA binding
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: NEMF binds Ala-charged tRNA, the molecular basis for alanine tailing of stalled nascent chains.
Reason: Core molecular function; directly demonstrated tRNA-Ala binding.
Supporting Evidence:
PMID:33909987
mediated by tRNA-Ala binding and Ala tailing
GO:1990112 RQC complex
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: Direct evidence for NEMF as an RQC complex component in mammalian cells.
Reason: Core; experimentally demonstrated RQC complex membership.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
Component of the ribosome quality control complex (RQC)
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
IDA
PMID:33406423
Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Mor... 		ACCEPT
Summary: NEMF-mediated CAT tailing promotes ubiquitination and proteasomal degradation of stalled nascent chains.
Reason: Core; CAT tailing facilitates ubiquitin-dependent degradation of stalled chains.
Supporting Evidence:
PMID:33406423
CAT tailing promotes ubiquitination of NCs for proteasomal degradation
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: NEMF directs Ala-tailed stalled chains to ubiquitin-dependent degradation via Listerin and via C-end-rule E3 ligases.
Reason: Core; experimentally supported role in ribosome-associated ubiquitin-dependent catabolism.
Supporting Evidence:
PMID:33909987
target them for degradation
GO:0065003 protein-containing complex assembly
IMP
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		KEEP AS NON CORE
Summary: NEMF promotes assembly of the RQC complex by recruiting and stabilizing LTN1 on the stalled 60S. This is the complex-assembly aspect of its RQC role rather than an independent function.
Reason: Supported by IMP, but it describes NEMF's contribution to RQC assembly (LTN1 recruitment); the informative core functions are 60S sensing, CAT tailing and tRNA binding.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
promotes the recruitment of LTN1 to stalled 60S subunits
GO:0005829 cytosol
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: Direct evidence for cytosolic localization of NEMF.
Reason: Correct compartment; NEMF acts in the cytosol on ribosomes.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:1990112 RQC complex
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: The cryo-EM structure resolves NEMF as part of the RQC complex bridging 60S, the P-site tRNA and LTN1.
Reason: Core; directly demonstrated structurally.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
Component of the ribosome quality control complex (RQC)
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
IDA
PMID:25578875
Structure and assembly pathway of the ribosome quality contr... 		ACCEPT
Summary: NEMF promotes ubiquitin-dependent degradation of stalled nascent chains by recruiting LTN1 to the 60S.
Reason: Core, experimentally supported defining biological process.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
as well as their ubiquitin-mediated proteasomal degradation
GO:0051168 nuclear export
IMP
PMID:16103875
Drosophila caliban, a nuclear export mediator, can function ... 		KEEP AS NON CORE
Summary: An older study (the source of the nuclear-export-mediator-factor name) implicated NEMF/Caliban in nuclear export and tumor suppression. UniProt records only an indirect role. This predates and is peripheral to NEMF's central RQC function.
Reason: Legacy/indirect role recorded by UniProt as an indirect role in nuclear export; not the core, extensively characterized RQC function. Full text not available for independent verification beyond the UniProt summary.
Supporting Evidence:
file:human/NEMF/NEMF-uniprot.txt
NEMF may also indirectly play a role in nuclear export
GO:0140708 CAT tailing
IDA
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic path... 		ACCEPT
Summary: Additional direct annotation of CAT tailing; NEMF adds non-templated alanine tails to stalled nascent chains.
Reason: Core catalytic activity of NEMF, directly demonstrated.
Supporting Evidence:
PMID:33909987
mediated by tRNA-Ala binding and Ala tailing

Core Functions

Adds non-templated C-terminal alanine (CAT/Ala) tails to stalled nascent polypeptides by binding aminoacyl(Ala)-tRNA and directing its delivery to the ribosomal A site in an mRNA- and 40S-independent manner.

Molecular Function:
alpha-aminoacyl-tRNA binding
Cellular Locations:
cytosolic ribosome
Supporting Evidence:
  • PMID:33909987
    mediated by tRNA-Ala binding and Ala tailing
  • file:human/NEMF/NEMF-uniprot.txt
    NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site

Binds the stalled 60S large ribosomal subunit by recognizing the exposed nascent- chain-conjugated P-site tRNA, sensing nascent-chain occupancy and recruiting/stabilizing the LTN1 ligase to assemble a functional RQC complex.

Molecular Function:
ribosomal large subunit binding
In Complex:
RQC complex
Supporting Evidence:
  • file:human/NEMF/NEMF-uniprot.txt
    NEMF specifically binds stalled 60S ribosomal subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety
  • file:human/NEMF/NEMF-uniprot.txt
    promotes the recruitment of LTN1 to stalled 60S subunits

Through CAT tailing, drives ribosome-associated ubiquitin-dependent degradation of incompletely synthesized nascent chains, both by exposing lysines for LTN1-dependent ubiquitination and by generating a C-terminal alanine degron for C-end-rule E3 ligases.

Directly Involved In:
CAT tailing
Cellular Locations:
cytosolic ribosome
Supporting Evidence:
  • PMID:33406423
    NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids
  • file:human/NEMF/NEMF-uniprot.txt
    as well as their ubiquitin-mediated proteasomal degradation

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
GO_REF:0000107
Automatic Assertion of Orthology
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16103875
Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells.
PMID:25578875
Structure and assembly pathway of the ribosome quality control complex.
  • NEMF senses nascent-chain occupancy of 60S via the exposed P-site tRNA and recruits/stabilizes Listerin, defining the RQC complex assembly pathway.
PMID:33406423
Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival.
  • Mammalian NEMF (RQC2 homolog) adds non-templated C-terminal alanine-rich (CAT) tails to nonstop translation products; CAT tailing promotes ubiquitination for proteasomal degradation, and failure causes nascent-chain aggregation and apoptosis.
PMID:33909987
Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing.
  • NEMF performs tRNA-Ala-dependent alanine tailing of stalled nascent chains; in addition to assisting Listerin, the Ala tail acts as a C-degron recognized by CRL2-KLHDC10 and RCHY1/PIRH2 C-end-rule E3 ligases.
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans.
  • Review summarizing RQC including NEMF/Rqc2 as the 60S-sensing, CAT-tailing RQC subunit.
Reactome:R-HSA-9948318
Reactome: NEMF cytosol localization
Reactome:R-HSA-9948360
Reactome: NEMF cytosol localization
Reactome:R-HSA-9948362
Reactome: NEMF cytosol localization
Reactome:R-HSA-9948427
Reactome: NEMF cytosol localization
Reactome:R-HSA-9948458
Reactome: NEMF cytosol localization
Reactome:R-HSA-9954723
Reactome: NEMF cytosol localization
Reactome:R-HSA-9954727
Reactome: NEMF cytosol localization
file:human/NEMF/NEMF-uniprot.txt
UniProt entry O60524 (NEMF_HUMAN), Ribosome quality control complex subunit NEMF
  • RQC complex subunit that senses stalled 60S via the nascent-chain-conjugated tRNA, recruits LTN1, and mediates CAT tailing (alanine tailing) of stalled nascent chains to promote their ubiquitin-dependent degradation via LTN1 (RQC-L) and C-end-rule E3 ligases (RQC-C); cytosolic.

Suggested Questions for Experts

Q: What determines the choice between the LTN1-dependent (RQC-L) and C-end-rule (RQC-C) degradation routes downstream of NEMF Ala tailing in mammalian cells?

Q: How do the disease-causing NEMF variants (IDDSAPN) mechanistically impair 60S sensing, LTN1 recruitment, or CAT tailing, and which deficit drives the neuropathy?

Suggested Experiments

Experiment: Reconstitute CAT tailing in vitro with purified human NEMF, 60S-nascent chain complexes, and charged tRNAs to quantify amino-acid selectivity (Ala vs Thr vs others) and its dependence on 40S/mRNA.

Experiment: Introduce patient-derived NEMF missense variants into cells and assay 60S binding, LTN1 recruitment, CAT-tail length/composition, and nascent-chain degradation to map genotype to molecular defect.

📚 Additional Documentation

Notes

(NEMF-notes.md)

NEMF (Rqc2/Tae2 ortholog) research notes

UniProt: O60524 (NEMF_HUMAN). "Nuclear Export Mediator Factor" / Ribosome quality control
complex subunit NEMF. Mammalian Rqc2/RQC2/Tae2 homolog. NEMF family.

Core function

NEMF is a key component of the RQC complex. It binds stalled 60S ribosomal subunits by
recognizing the exposed nascent-chain-conjugated (P-site peptidyl) tRNA, recruits/stabilizes
LTN1/Listerin, and mediates CAT tailing — non-templated, mRNA- and 40S-independent C-terminal
elongation of stalled nascent chains using mainly Ala-charged tRNA delivered to the A-site.

  • UniProt FUNCTION: "Within the RQC complex, NEMF specifically binds stalled 60S ribosomal
    subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety and promotes the
    recruitment of LTN1 to stalled 60S subunits (PubMed:25578875)."
  • UniProt FUNCTION: "NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A-
    site and directing the elongation of stalled nascent chains independently of mRNA or 40S
    subunits, leading to non-templated C-terminal alanine extensions (CAT tails)."
  • PMID:33406423
  • PMID:33909987

Mechanistic role in two RQC branches

  • RQC-L (canonical): CAT tailing exposes lysines for LTN1-dependent ubiquitination.
  • RQC-C (alternative): Ala tail forms a C-degron recognized by CRL2(KLHDC10) and RCHY1/PIRH2
    C-end-rule E3 ligases.
  • PMID:33909987

MF annotations

  • GO:0000049 tRNA binding (IBA) — supported; NEMF binds peptidyl-tRNA and recruits aminoacyl-tRNA.
  • GO:1904678 alpha-aminoacyl-tRNA binding (IDA, PMID:33406423, PMID:33909987) — core; binds
    Ala-charged tRNA for CAT-tailing.
  • GO:0043023 ribosomal large subunit binding (IDA/IBA) — core; binds 60S.

BP annotations

  • GO:0140708 CAT tailing (IDA PMID:33406423, PMID:33909987) — CORE, NEMF-defining activity.
  • GO:0072344 rescue of stalled cytosolic ribosome — core RQC.
  • GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process — core.
  • GO:0065003 protein-containing complex assembly (IMP PMID:25578875) — NEMF promotes RQC
    assembly (recruits LTN1); KEEP_AS_NON_CORE (this is the complex-assembly aspect of its role).

Nuclear export (legacy)

  • GO:0051168 nuclear export (IMP PMID:16103875) — older name "nuclear export mediator factor";
    UniProt notes "NEMF may also indirectly play a role in nuclear export (PubMed:16103875)".
    This predates the RQC characterization. PMID:16103875 not cached. Keep as NON_CORE; the
    predominant, well-supported function is cytoplasmic RQC. Treat as minor/contested role.
  • Nucleus localization (GO:0005634 IEA, GO_REF:0000044) reflects the legacy "nuclear export"
    role; UniProt lists Nucleus by ECO:0000305|PubMed:16103875. KEEP_AS_NON_CORE — predominant
    localization is cytosol/cytosolic ribosome.

Complex / localization

  • RQC complex (LTN1 + TCF25 + NEMF) on 60S. Cytoplasm, cytosol (PubMed:25578875).
  • Disease: biallelic NEMF variants cause IDDSAPN (intellectual disability + axonal neuropathy);
    Listerin/NEMF loss → neurodegeneration in mice. (background)

Actions summary

  • Core MFs: GO:1904678 alpha-aminoacyl-tRNA binding; GO:0000049 tRNA binding; GO:0043023 60S binding.
  • Core BPs: GO:0140708 CAT tailing; GO:0072344 rescue; GO:1990116 RQC catabolism.
  • nucleus / nuclear export -> KEEP_AS_NON_CORE.
  • cytosol IEA/TAS, cytosolic ribosome IDA, RQC complex -> ACCEPT.
  • protein-containing complex assembly -> KEEP_AS_NON_CORE.

Pn Notes

(NEMF-pn-notes.md)

NEMF PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O60524
  • 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: NEMF (Nuclear Export Mediator Factor; also called RQC2, the mammalian ortholog of yeast Rqc2/Tae2 and bacterial RqcH) is a core subunit of the ribosome-associated quality control (RQC) complex that acts on stalled 60S large ribosomal subunits. After an aberrant ribosome stalls and is split, NEMF recognizes the exposed nascent-chain-conjugated (peptidyl) tRNA in the 60S subunit, which allows it to discriminate occupied from empty 60S, and it recruits and stabilizes the E3 ubiquitin ligase LTN1/Listerin. NEMF additionally catalyzes CAT tailing, in which (in an mRNA- and 40S-independent manner) it delivers mainly alanine-charged tRNA (and other aminoacyl-tRNAs) to the ribosomal A site and directs non-templated C-terminal elongation of the stalled nascent chain, generating C-terminal alanine/threonine (CAT) tails. These tails promote degradation of the stalled chain by two routes. In the canonical RQC-L pathway they expose buried lysines for LTN1-dependent ubiquitination, and in the alternative RQC-C pathway they form a C-terminal alanine degron recognized by C-end-rule E3 ligases (CRL2-KLHDC10 and RCHY1/PIRH2). NEMF acts in the cytosol on cytosolic ribosomes; loss of NEMF function causes accumulation of toxic, aggregation-prone nascent chains, and biallelic NEMF variants cause an autosomal-recessive neurodevelopmental disorder with peripheral neuropathy.
  • Existing/core annotation action counts: ACCEPT: 33; KEEP_AS_NON_CORE: 3

PN Consistency Summary

  • Consistency: Strong. Deep-research notes, review YAML and PN dossier all agree NEMF is the mammalian Rqc2/RQC2 ortholog: core RQC subunit that senses stalled 60S via the nascent-chain-conjugated P-site tRNA, recruits LTN1, and catalyzes CAT/Ala tailing (GO:0140708) of stalled nascent chains. PN placement under Ribosome-associated QC matches.
  • PN story / NEW pressure: PN projects GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins) at the group level. Verified real and non-obsolete via OLS. Critically, OLS ancestor check shows the review's RQC terms GO:1990116 (ribosome-associated ubiquitin-dependent protein catabolic process) and GO:0072344 (rescue of stalled cytosolic ribosome) do NOT have GO:0006515 as an ancestor (they sit in the ubiquitin-catabolic branch). So GO:0006515 is a genuinely distinct, complementary QC-aspect term not currently captured. Conclusion: ADD GO:0006515 (involved_in) is defensible for NEMF and not redundant with existing annotations; the group projection is well justified ("GO lacks a dedicated RQC term" rationale is accurate — RQC is captured only via the catabolic/rescue children).
  • Evidence alignment: Concordant and rich. Review anchors CAT tailing to PMID:33406423 and PMID:33909987 (both VERIFIED), 60S sensing/LTN1 recruitment to PMID:25578875, RQC review PMID:35452614. PN row carries no titles; review is broader. No divergence.
  • Verdict: Consistent, high-quality; PN projection of GO:0006515 is a defensible ADD (distinct QC aspect, verified absent from GOA and not an ancestor of existing terms). Recommended edits: Add GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins, involved_in) to NEMF review to mirror the PN projection [YAML].

Full Consistency Review

  • UniProt: O60524 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes ; PN-node mapping: type other RQC processes→no_mapping; group Ribosome-associated QC→GO:0006515 protein quality control for misfolded or incompletely synthesized proteins (ok_for_propagation, new_to_goa)
  • Consistency: Strong. Deep-research notes, review YAML and PN dossier all agree NEMF is the mammalian Rqc2/RQC2 ortholog: core RQC subunit that senses stalled 60S via the nascent-chain-conjugated P-site tRNA, recruits LTN1, and catalyzes CAT/Ala tailing (GO:0140708) of stalled nascent chains. PN placement under Ribosome-associated QC matches.
  • PN story / NEW pressure: PN projects GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins) at the group level. Verified real and non-obsolete via OLS. Critically, OLS ancestor check shows the review's RQC terms GO:1990116 (ribosome-associated ubiquitin-dependent protein catabolic process) and GO:0072344 (rescue of stalled cytosolic ribosome) do NOT have GO:0006515 as an ancestor (they sit in the ubiquitin-catabolic branch). So GO:0006515 is a genuinely distinct, complementary QC-aspect term not currently captured. Conclusion: ADD GO:0006515 (involved_in) is defensible for NEMF and not redundant with existing annotations; the group projection is well justified ("GO lacks a dedicated RQC term" rationale is accurate — RQC is captured only via the catabolic/rescue children).
  • Mapping strategy: Reasonable. type→no_mapping (correct: "other RQC processes" is a heterogeneous bucket); group→GO:0006515 is the safe broader QC target. Not too broad to project for a bona fide RQC factor. No change warranted.
  • Evidence alignment: Concordant and rich. Review anchors CAT tailing to PMID:33406423 and PMID:33909987 (both VERIFIED), 60S sensing/LTN1 recruitment to PMID:25578875, RQC review PMID:35452614. PN row carries no titles; review is broader. No divergence.
  • Verdict: Consistent, high-quality; PN projection of GO:0006515 is a defensible ADD (distinct QC aspect, verified absent from GOA and not an ancestor of existing terms). Recommended edits: Add GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins, involved_in) to NEMF review to mirror the PN projection [YAML].

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/NEMF/NEMF-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

  • UniProt: O60524
  • 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 (1)

  • 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: O60524
gene_symbol: NEMF
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NEMF (Nuclear Export Mediator Factor; also called RQC2, the mammalian ortholog of yeast Rqc2/Tae2 and bacterial RqcH) is a core subunit of the ribosome-associated quality control (RQC) complex that acts on stalled 60S large ribosomal subunits. After an aberrant ribosome stalls and is split, NEMF recognizes the exposed nascent-chain-conjugated (peptidyl) tRNA in the 60S subunit, which allows it to discriminate occupied from empty 60S, and it recruits and stabilizes the E3 ubiquitin ligase LTN1/Listerin. NEMF additionally catalyzes CAT tailing, in which (in an mRNA- and 40S-independent manner) it delivers mainly alanine-charged tRNA (and other aminoacyl-tRNAs) to the ribosomal A site and directs non-templated C-terminal elongation of the stalled nascent chain, generating C-terminal alanine/threonine (CAT) tails. These tails promote degradation of the stalled chain by two routes. In the canonical RQC-L pathway they expose buried lysines for LTN1-dependent ubiquitination, and in the alternative RQC-C pathway they form a C-terminal alanine degron recognized by C-end-rule E3 ligases (CRL2-KLHDC10 and RCHY1/PIRH2). NEMF acts in the cytosol on cytosolic ribosomes; loss of NEMF function causes accumulation of toxic, aggregation-prone nascent chains, and biallelic NEMF variants cause an autosomal-recessive neurodevelopmental disorder with peripheral neuropathy.
alternative_products:
- name: '1'
  id: O60524-1
- name: '2'
  id: O60524-2
  sequence_note: VSP_008396, VSP_010462
- name: '3'
  id: O60524-3
  sequence_note: VSP_041066
- name: '4'
  id: O60524-4
  sequence_note: VSP_041064
- name: '5'
  id: O60524-5
  sequence_note: VSP_041065
existing_annotations:
- term:
    id: GO:0000049
    label: tRNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: NEMF binds tRNA - both the nascent-chain-conjugated peptidyl-tRNA it uses to sense stalled 60S and the aminoacyl-tRNA it delivers for CAT tailing. tRNA binding is conserved across the NEMF/Rqc2 family.
    action: ACCEPT
    reason: Well supported; the more specific alpha-aminoacyl-tRNA binding (GO:1904678) is also annotated. tRNA binding is integral to NEMF's 60S sensing and CAT-tailing activities.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF specifically binds stalled 60S ribosomal subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: NEMF binds the stalled 60S large ribosomal subunit, making multiple contacts with 60S and the P-site tRNA. This is core to its RQC function.
    action: ACCEPT
    reason: Directly demonstrated structurally and biochemically; binding 60S is the basis for NEMF's nascent-chain sensing.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF specifically binds stalled 60S ribosomal subunits
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: NEMF is one of the three defining subunits of the RQC complex (LTN1, TCF25, NEMF) on the 60S subunit.
    action: ACCEPT
    reason: Directly demonstrated; conserved RQC complex membership.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: NEMF participates in resolving stalled ribosomes by sensing 60S-nascent chain complexes and triggering downstream degradation/CAT-tailing.
    action: ACCEPT
    reason: Conserved and experimentally supported RQC role.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: frees 60S subunit ribosomes from the stalled translation complex
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: By recruiting LTN1 and CAT-tailing nascent chains to promote their ubiquitination, NEMF is integral to ribosome-associated ubiquitin-dependent degradation.
    action: ACCEPT
    reason: Conserved and experimentally supported; NEMF promotes degradation of stalled nascent chains.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: as well as their ubiquitin-mediated proteasomal degradation
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization derives from the legacy nuclear-export-mediator-factor role (PubMed:16103875), predating NEMF's characterization as an RQC factor. The predominant, well-supported localization is cytosolic.
    action: KEEP_AS_NON_CORE
    reason: UniProt lists Nucleus by ECO:0000305 based on the older nuclear-export role, but the core, extensively documented function of NEMF is cytoplasmic RQC; nuclear localization is peripheral.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF may also indirectly play a role in nuclear export
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytosolic localization, consistent with the experimentally documented site of NEMF action.
    action: ACCEPT
    reason: Correct compartment; redundant with IDA cytosol evidence.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0140708
    label: CAT tailing
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (ARBA, ortholog) assignment of CAT tailing, the signature catalytic activity of NEMF, consistent with direct experimental IDA evidence.
    action: ACCEPT
    reason: Correct core process; NEMF is the mammalian enzyme that adds C-terminal alanine (CAT) tails to stalled nascent chains.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of the RQC ubiquitin-dependent catabolic process, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct core process; redundant with IDA evidence.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: as well as their ubiquitin-mediated proteasomal degradation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948318
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948360
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948362
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948427
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948458
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9954723
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9954727
  qualifier: located_in
  review:
    summary: Reactome curation of NEMF cytosolic localization.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental cytosol annotations.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: involved_in
  review:
    summary: Review-based (ComplexPortal NAS) assertion of NEMF's RQC rescue role.
    action: ACCEPT
    reason: Consistent with experimentally supported RQC function.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: part_of
  review:
    summary: Review-based (ComplexPortal NAS) assertion of NEMF as an RQC complex subunit.
    action: ACCEPT
    reason: Consistent with experimentally demonstrated RQC complex membership.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: involved_in
  review:
    summary: Review-based (ComplexPortal NAS) assertion of NEMF's RQC catabolic role.
    action: ACCEPT
    reason: Consistent with the experimentally supported process.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: is_active_in
  review:
    summary: NEMF acts on the cytosolic 60S ribosome; the cryo-EM RQC structure places NEMF on the 60S subunit contacting the P-site tRNA.
    action: ACCEPT
    reason: Directly demonstrated; NEMF functions while bound to the cytosolic ribosome.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF specifically binds stalled 60S ribosomal subunits
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: is_active_in
  review:
    summary: NEMF acts on the cytosolic ribosome during alanine tailing of stalled nascent chains.
    action: ACCEPT
    reason: Directly demonstrated; NEMF's Ala-tailing activity occurs on 60S-nascent chain complexes.
    supported_by:
    - reference_id: PMID:33909987
      supporting_text: mediated by tRNA-Ala binding and Ala tailing
- term:
    id: GO:0043023
    label: ribosomal large subunit binding
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: enables
  review:
    summary: Direct evidence that NEMF binds the 60S large subunit, making simultaneous contacts with 60S and the peptidyl-tRNA.
    action: ACCEPT
    reason: Core; experimentally demonstrated 60S binding underlies NEMF's nascent-chain sensing.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF specifically binds stalled 60S ribosomal subunits
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: involved_in
  review:
    summary: Direct experimental evidence for NEMF's role in resolving stalled 60S-nascent chain complexes within RQC.
    action: ACCEPT
    reason: Core, experimentally supported RQC/rescue function.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: frees 60S subunit ribosomes from the stalled translation complex
- term:
    id: GO:0140708
    label: CAT tailing
  evidence_type: IDA
  original_reference_id: PMID:33406423
  qualifier: involved_in
  review:
    summary: Direct evidence that mammalian NEMF modifies stalled (nonstop) translation products with non-templated C-terminal alanine-rich (CAT) tails. This is NEMF's signature catalytic activity.
    action: ACCEPT
    reason: Core molecular activity demonstrated directly in mammalian cells; NEMF is the CAT- tailing enzyme.
    supported_by:
    - reference_id: PMID:33406423
      supporting_text: NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids
- term:
    id: GO:0140708
    label: CAT tailing
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: involved_in
  review:
    summary: Direct evidence that NEMF performs alanine tailing of stalled nascent chains via tRNA-Ala binding, in both Listerin-dependent and Listerin-independent routes.
    action: ACCEPT
    reason: Core; experimentally demonstrated CAT/Ala tailing activity.
    supported_by:
    - reference_id: PMID:33909987
      supporting_text: mammalian NEMF has an additional, Listerin-independent proteolytic role, which, as in bacteria, is mediated by tRNA-Ala binding and Ala tailing
- term:
    id: GO:1904678
    label: alpha-aminoacyl-tRNA binding
  evidence_type: IDA
  original_reference_id: PMID:33406423
  qualifier: enables
  review:
    summary: NEMF binds aminoacyl-tRNA (mainly Ala-charged) to deliver it to the A site during CAT tailing. This is the molecular function underlying its tailing activity.
    action: ACCEPT
    reason: Core molecular function; directly supports the CAT-tailing mechanism.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site
- term:
    id: GO:1904678
    label: alpha-aminoacyl-tRNA binding
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: enables
  review:
    summary: NEMF binds Ala-charged tRNA, the molecular basis for alanine tailing of stalled nascent chains.
    action: ACCEPT
    reason: Core molecular function; directly demonstrated tRNA-Ala binding.
    supported_by:
    - reference_id: PMID:33909987
      supporting_text: mediated by tRNA-Ala binding and Ala tailing
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: part_of
  review:
    summary: Direct evidence for NEMF as an RQC complex component in mammalian cells.
    action: ACCEPT
    reason: Core; experimentally demonstrated RQC complex membership.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: Component of the ribosome quality control complex (RQC)
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:33406423
  qualifier: involved_in
  review:
    summary: NEMF-mediated CAT tailing promotes ubiquitination and proteasomal degradation of stalled nascent chains.
    action: ACCEPT
    reason: Core; CAT tailing facilitates ubiquitin-dependent degradation of stalled chains.
    supported_by:
    - reference_id: PMID:33406423
      supporting_text: CAT tailing promotes ubiquitination of NCs for proteasomal degradation
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: involved_in
  review:
    summary: NEMF directs Ala-tailed stalled chains to ubiquitin-dependent degradation via Listerin and via C-end-rule E3 ligases.
    action: ACCEPT
    reason: Core; experimentally supported role in ribosome-associated ubiquitin-dependent catabolism.
    supported_by:
    - reference_id: PMID:33909987
      supporting_text: target them for degradation
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: IMP
  original_reference_id: PMID:25578875
  qualifier: involved_in
  review:
    summary: NEMF promotes assembly of the RQC complex by recruiting and stabilizing LTN1 on the stalled 60S. This is the complex-assembly aspect of its RQC role rather than an independent function.
    action: KEEP_AS_NON_CORE
    reason: Supported by IMP, but it describes NEMF's contribution to RQC assembly (LTN1 recruitment); the informative core functions are 60S sensing, CAT tailing and tRNA binding.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: promotes the recruitment of LTN1 to stalled 60S subunits
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: located_in
  review:
    summary: Direct evidence for cytosolic localization of NEMF.
    action: ACCEPT
    reason: Correct compartment; NEMF acts in the cytosol on ribosomes.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytosol'
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: part_of
  review:
    summary: The cryo-EM structure resolves NEMF as part of the RQC complex bridging 60S, the P-site tRNA and LTN1.
    action: ACCEPT
    reason: Core; directly demonstrated structurally.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: Component of the ribosome quality control complex (RQC)
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25578875
  qualifier: involved_in
  review:
    summary: NEMF promotes ubiquitin-dependent degradation of stalled nascent chains by recruiting LTN1 to the 60S.
    action: ACCEPT
    reason: Core, experimentally supported defining biological process.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: as well as their ubiquitin-mediated proteasomal degradation
- term:
    id: GO:0051168
    label: nuclear export
  evidence_type: IMP
  original_reference_id: PMID:16103875
  qualifier: involved_in
  review:
    summary: An older study (the source of the nuclear-export-mediator-factor name) implicated NEMF/Caliban in nuclear export and tumor suppression. UniProt records only an indirect role. This predates and is peripheral to NEMF's central RQC function.
    action: KEEP_AS_NON_CORE
    reason: Legacy/indirect role recorded by UniProt as an indirect role in nuclear export; not the core, extensively characterized RQC function. Full text not available for independent verification beyond the UniProt summary.
    supported_by:
    - reference_id: file:human/NEMF/NEMF-uniprot.txt
      supporting_text: NEMF may also indirectly play a role in nuclear export
- term:
    id: GO:0140708
    label: CAT tailing
  evidence_type: IDA
  original_reference_id: PMID:33909987
  qualifier: involved_in
  review:
    summary: Additional direct annotation of CAT tailing; NEMF adds non-templated alanine tails to stalled nascent chains.
    action: ACCEPT
    reason: Core catalytic activity of NEMF, directly demonstrated.
    supported_by:
    - reference_id: PMID:33909987
      supporting_text: mediated by tRNA-Ala binding and Ala tailing
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic Assertion of Orthology
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16103875
  title: Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells.
  full_text_unavailable: true
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of the nuclear-export-mediator-factor name; predates the RQC characterization. UniProt records only an indirect nuclear-export role. Not cached; relevance to the core RQC function is low.
- id: PMID:25578875
  title: Structure and assembly pathway of the ribosome quality control complex.
  findings:
  - statement: NEMF senses nascent-chain occupancy of 60S via the exposed P-site tRNA and recruits/stabilizes Listerin, defining the RQC complex assembly pathway.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural study establishing NEMF's 60S sensing and LTN1 recruitment.
- id: PMID:33406423
  title: Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival.
  findings:
  - statement: Mammalian NEMF (RQC2 homolog) adds non-templated C-terminal alanine-rich (CAT) tails to nonstop translation products; CAT tailing promotes ubiquitination for proteasomal degradation, and failure causes nascent-chain aggregation and apoptosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct demonstration of NEMF CAT-tailing in mammalian cells and its physiological/neuronal significance.
- id: PMID:33909987
  title: Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing.
  findings:
  - statement: NEMF performs tRNA-Ala-dependent alanine tailing of stalled nascent chains; in addition to assisting Listerin, the Ala tail acts as a C-degron recognized by CRL2-KLHDC10 and RCHY1/PIRH2 C-end-rule E3 ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the Listerin-independent RQC-C pathway downstream of NEMF Ala tailing.
- id: PMID:35452614
  title: Ribosome-associated quality-control mechanisms from bacteria to humans.
  findings:
  - statement: Review summarizing RQC including NEMF/Rqc2 as the 60S-sensing, CAT-tailing RQC subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Authoritative RQC review used by ComplexPortal for NAS annotations.
- id: Reactome:R-HSA-9948318
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948360
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948362
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948427
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948458
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9954723
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: Reactome:R-HSA-9954727
  title: 'Reactome: NEMF cytosol localization'
  findings: []
- id: file:human/NEMF/NEMF-uniprot.txt
  title: UniProt entry O60524 (NEMF_HUMAN), Ribosome quality control complex subunit NEMF
  findings:
  - statement: RQC complex subunit that senses stalled 60S via the nascent-chain-conjugated tRNA, recruits LTN1, and mediates CAT tailing (alanine tailing) of stalled nascent chains to promote their ubiquitin-dependent degradation via LTN1 (RQC-L) and C-end-rule E3 ligases (RQC-C); cytosolic.
    reference_section_type: OTHER
core_functions:
- description: Adds non-templated C-terminal alanine (CAT/Ala) tails to stalled nascent polypeptides by binding aminoacyl(Ala)-tRNA and directing its delivery to the ribosomal A site in an mRNA- and 40S-independent manner.
  molecular_function:
    id: GO:1904678
    label: alpha-aminoacyl-tRNA binding
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:33909987
    supporting_text: mediated by tRNA-Ala binding and Ala tailing
  - reference_id: file:human/NEMF/NEMF-uniprot.txt
    supporting_text: NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A- site
- description: Binds the stalled 60S large ribosomal subunit by recognizing the exposed nascent- chain-conjugated P-site tRNA, sensing nascent-chain occupancy and recruiting/stabilizing the LTN1 ligase to assemble a functional RQC complex.
  molecular_function:
    id: GO:0043023
    label: ribosomal large subunit binding
  in_complex:
    id: GO:1990112
    label: RQC complex
  supported_by:
  - reference_id: file:human/NEMF/NEMF-uniprot.txt
    supporting_text: NEMF specifically binds stalled 60S ribosomal subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety
  - reference_id: file:human/NEMF/NEMF-uniprot.txt
    supporting_text: promotes the recruitment of LTN1 to stalled 60S subunits
- description: Through CAT tailing, drives ribosome-associated ubiquitin-dependent degradation of incompletely synthesized nascent chains, both by exposing lysines for LTN1-dependent ubiquitination and by generating a C-terminal alanine degron for C-end-rule E3 ligases.
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:33406423
    supporting_text: NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids
  - reference_id: file:human/NEMF/NEMF-uniprot.txt
    supporting_text: as well as their ubiquitin-mediated proteasomal degradation
  directly_involved_in:
  - id: GO:0140708
    label: CAT tailing
proposed_new_terms: []
suggested_questions:
- question: What determines the choice between the LTN1-dependent (RQC-L) and C-end-rule (RQC-C) degradation routes downstream of NEMF Ala tailing in mammalian cells?
- question: How do the disease-causing NEMF variants (IDDSAPN) mechanistically impair 60S sensing, LTN1 recruitment, or CAT tailing, and which deficit drives the neuropathy?
suggested_experiments:
- description: Reconstitute CAT tailing in vitro with purified human NEMF, 60S-nascent chain complexes, and charged tRNAs to quantify amino-acid selectivity (Ala vs Thr vs others) and its dependence on 40S/mRNA.
- description: Introduce patient-derived NEMF missense variants into cells and assay 60S binding, LTN1 recruitment, CAT-tail length/composition, and nascent-chain degradation to map genotype to molecular defect.