Nuclear Localization Sequence Binding — Obsoletion & Replacement
Overview
A GO obsoletion proposal will retire GO:0008139 nuclear localization
sequence binding (MF) and replace it with GO:0140142 nucleocytoplasmic
carrier activity. This is part of the broader "signal sequence binding
and children" refactor in go-ontology#31419 (CLOSED), which moves the
sub-tree of GO:0005048 signal sequence binding from a generic binding
formulation to a non-binding receptor / carrier formulation. The sibling
"mitochondrion targeting sequence binding" obsoletion (go-annotation#6437)
is tracked separately in
projects/MITOCHONDRION_TARGETING_SEQUENCE_BINDING_OBSOLETION.md.
The replacement term GO:0140142 nucleocytoplasmic carrier activity is
defined as "Binding to and carrying a cargo between the nucleus and the
cytoplasm by moving along with the cargo. The cargo can be either a RNA or
a protein." This is the canonical importin / karyopherin / exportin MF and
fits the experimental annotations on KPNA / KPNB / TNPO / IPO / PSE1 /
KAP104 / KAP123 / MTR10 etc. However, several GO:0008139 annotations are
on proteins that bind an NLS without carrying it across the
nuclear pore (e.g. nucleoporins Nup98/Nup153/Nup214/Nup58, the nucleolar
NSR1, IκBα/NFKBIA, BRAP, Su(fu), CABP1, Nolc1). For these, the upstream
proposal is to evaluate case-by-case — some will move to GO:0140142,
others to alternative MFs (e.g. structural constituent of nuclear pore,
GO:0050839 cell adhesion molecule binding-style cargo-binding terms, or
removal when the assertion no longer holds under current evidence
standards).
This project queues the affected genes for prospective review, since
none of the directly annotated genes are currently in this repository.
Upstream tickets
- Annotation tracker: geneontology/go-annotation#6435 (opened 2026-05-27)
- Ontology ticket: geneontology/go-ontology#31419 (CLOSED — "Review 'signal sequence binding' and children", high priority, MF refactoring)
- Sibling sub-issues from the same refactor that are tracked here:
- go-annotation#6437 mitochondrion targeting sequence binding →
MITOCHONDRION_TARGETING_SEQUENCE_BINDING_OBSOLETION - go-annotation#6383 ER-PM tethering (different parent, same refactor wave) →
ER_PM_TETHERING_OBSOLETION - Peroxisome targeting signal binding (also under
GO:0005048) →PEROXISOME_TARGETING_SIGNAL_OBSOLETION - Affected annotations spreadsheet (upstream): https://docs.google.com/spreadsheets/d/1NLoo-WPT-6YpYDKVbUqrOHZSnOkIbDVtj4OB2s5Cx3M/edit?gid=779903919
- FYPO usage: FYPO:0007070 uses GO:0008139 as a UbergraphImplementation relationship object (will need to follow the GO change).
Obsoletion plan (per upstream)
| Obsoleted term | ID | Replacement |
|---|---|---|
| nuclear localization sequence binding (MF) | GO:0008139 | GO:0140142 nucleocytoplasmic carrier activity (case-by-case; some annotations may map to a different MF or be removed) |
Term status verified in OLS on 2026-06-01:
- GO:0008139 (
nuclear localization sequence binding) — live (isObsolete: false); synonyms: NLS binding, nuclear localization signal binding, nuclear localisation sequence binding. - GO:0140142 (
nucleocytoplasmic carrier activity) — live, has children; synonyms: miRNA transporter activity, nucleocytoplasmic importin/exportin activity, pre-miRNA transporter activity. - The ontology ticket #31419 is CLOSED, so the upstream agreement that GO:0008139 should be obsoleted is settled; the per-annotation remapping work in go-annotation#6435 is still open.
Affected experimental / curated annotations
The upstream issue tallies direct annotations by source DB:
| Source | Count | Status |
|---|---|---|
| UniProt | 10 | Open |
| SGD | 7 | Open |
| RGD | 6 | Open |
| PINC | 5 | Open |
| FlyBase | 2 | Open |
| ParkinsonsUK-UCL | 2 | Open |
| MGI | 1 | Open |
| PomBase | 1 | DONE (struck through upstream) |
Pulled via QuickGO REST on 2026-06-01 (manual + experimental evidence
filters, plus PINC ECO:0000304 author-statement entries):
UniProt (10)
| # | Accession | Symbol | Organism (taxon) | Evidence | Reference |
|---|---|---|---|---|---|
| 1 | F4JL11 | IMPA2 | A. thaliana (3702) | IMP | PMID:37676567 |
| 2 | O00629 | KPNA4 | H. sapiens (9606) | IDA | PMID:20818336 |
| 3 | O00629 | KPNA4 | H. sapiens (9606) | IDA | PMID:38512451 |
| 4 | O88751 | Cabp1 | R. norvegicus (10116) | IDA | PMID:18303947 |
| 5 | P25963 | NFKBIA (IκBα) | H. sapiens (9606) | IPI | PMID:1493333 |
| 6 | P52292 | KPNA2 | H. sapiens (9606) | IDA | PMID:17324944 |
| 7 | P52292 | KPNA2 | H. sapiens (9606) | IDA | PMID:28991411 |
| 8 | Q19969 | ima-3 | C. elegans (6239) | IDA | PMID:31417366 |
| 9 | Q8TEX9 | IPO4 | H. sapiens (9606) | IDA | PMID:17682055 |
| 10 | Q96321 | IMPA1 | A. thaliana (3702) | IMP | PMID:37676567 |
Accession spot-checks (UniProt REST, 2026-06-01): Q96321 resolves to
IMPA1_ARATH (Importin subunit alpha-1, A. thaliana, taxon 3702 — gene
names IMPA1 KAP1 At3g06720); F4JL11 resolves to F4JL11_ARATH
(Importin alpha isoform 2, A. thaliana, taxon 3702). Both accessions
match the table rows above.
SGD (7) — all S. cerevisiae (taxon 559292)
| # | Accession | Symbol | Evidence | Reference |
|---|---|---|---|---|
| 1 | P27476 | NSR1 | IDA | PMID:1706724 |
| 2 | P32337 | PSE1 / KAP121 | IDA | PMID:11694505 |
| 3 | P38217 | KAP104 | IDA | PMID:9488461 |
| 4 | P38748 | ETP1 | IDA | PMID:9497340 |
| 5 | P40069 | KAP123 | IDA | PMID:11694505 |
| 6 | Q02932 | KAP120 | IDA | PMID:20219973 |
| 7 | Q99189 | MTR10 / KAP111 | IDA | PMID:9545233 |
RGD (6 manual/experimental) — R. norvegicus (taxon 10116)
| # | Accession | Symbol | Evidence | Reference |
|---|---|---|---|---|
| 1 | D4ACK1 | Nup214 | IDA | PMID:7878057 |
| 2 | O08984 | Lbr | IPI | PMID:8486604 |
| 3 | P41777 | Nolc1 | IDA | PMID:1623516 |
| 4 | P49791 | Nup153 | IDA | PMID:7878057 |
| 5 | P49793 | Nup98 | IDA | PMID:7878057 |
| 6 | P70581 | Nup58 | IDA | PMID:8707840 |
(RGD also has 5 additional ECO:0000266 ortholog-projection entries on
Brap, Ipo4, Kpna4, Nfkbia, Kpna2 against GO_REF:0000121 — these follow
the manual annotations on the corresponding human genes and will
update automatically.)
PINC (5) — all H. sapiens (taxon 9606), ECO:0000304 (TAS)
| # | Accession | Symbol | Reference |
|---|---|---|---|
| 1 | O00505 | KPNA3 | PMID:9435235 |
| 2 | O14787 | TNPO2 | PMID:9298975 |
| 3 | P52294 | KPNA1 | PMID:7754385 |
| 4 | Q14974 | KPNB1 | PMID:7627554 |
| 5 | Q92973 | TNPO1 | PMID:8808633 |
FlyBase (2) — D. melanogaster (taxon 7227)
| # | Accession | Symbol | Evidence | Reference |
|---|---|---|---|---|
| 1 | O76521 | Kap-alpha1 | IDA | PMID:26887950 |
| 2 | Q9VG38 | Su(fu) | IPI | PMID:24413177 |
(A third FlyBase entry, Q9VRV8 Tnpo, is ISS — follows manual human TNPO1/2.)
ParkinsonsUK-UCL (2)
| # | Accession | Symbol | Organism | Evidence | Reference |
|---|---|---|---|---|---|
| 1 | O88751 | Cabp1 | R. norvegicus | IDA | PMID:18303947 |
| 2 | P83953 | Kpna1 | R. norvegicus | IDA | PMID:18303947 |
MGI (1)
| # | Accession | Symbol | Organism | Evidence | Reference |
|---|---|---|---|---|---|
| 1 | Q7Z569 | BRAP | H. sapiens (9606) | IDA | PMID:9497340 |
The MGI source / human accession combination is intentional, not a
transcription error: Q7Z569 resolves to BRAP_HUMAN (BRCA1-associated
protein, taxon 9606) per UniProt REST (2026-06-01), and the IDA
annotation was contributed to the human gene by an MGI curator working
from Li et al. 1998 (PMID:9497340, J. Biol. Chem. — the paper that
originally identified BRAP as a cytoplasmic NLS-binding factor). MGI
also holds the corresponding ISS annotation on mouse Brap (Q99MP8),
which follows the human IDA and is noted below.
(Q99MP8 mouse Brap is ISS and follows automatically.)
PomBase — DONE upstream
| # | Accession | Symbol | Organism | Evidence | Reference | Status |
|---|---|---|---|---|---|---|
| ✓ | O14063 | cut15 | S. pombe (taxon 284812) | IDA | PMID:9740803 | already remapped per upstream |
IEA / IBA scope (not enumerated)
QuickGO reports 18,125 total annotations to GO:0008139 across all
sources. The bulk are IEA ortholog projections (GO_REF:0000120 /
GO_REF:0000117) and IBA PAINT projections (GO_REF:0000033) — the IBA
projections fan out from the experimentally annotated importin/karyopherin
genes above. Once the manual annotations are remapped to GO:0140142, the
IBA/IEA fanout will be regenerated automatically by PAINT and the UniProt
inference pipeline.
Mappings flagged for redirection
The upstream issue body explicitly flags one InterPro2GO mapping:
| Source | Mapping ID | Description | Current target | Action |
|---|---|---|---|---|
| InterPro2GO | IPR024882 | Nucleoporin p58/p45/NUP49 | GO:0008139 | redirect (likely structural constituent of nuclear pore complex GO:0017056 rather than carrier activity, since p58/p45/NUP49 are pore components not importins) |
No UniRule or UniProt-Keywords mappings to GO:0008139 are listed upstream.
The FYPO term FYPO:0007070 uses GO:0008139 as a relationship object
in its UbergraphImplementation — it will need to follow the GO change
when the obsoletion is implemented.
Impact on this repo
None of the affected genes are currently reviewed here (searches for
KPNA1, KPNA2, KPNA3, KPNA4, KPNB1, TNPO1, TNPO2, IPO4, IMPA1, IMPA2,
NFKBIA, BRAP, Cabp1, Su(fu), Kap-alpha1, NSR1, PSE1, KAP104, KAP120,
KAP123, MTR10, ETP1, Nup58, Nup98, Nup153, Nup214, Nolc1, Lbr, cut15,
ima-3 returned no matches under genes/ on 2026-06-01). This means
no existing reviews need refresh for the obsoletion itself; the
project is a queueing exercise that lines up the importin/karyopherin
family for prospective review.
Scope
- Organisms: Human (10 direct: KPNA1-4, KPNB1, TNPO1, TNPO2, IPO4,
NFKBIA, BRAP), S. cerevisiae (7), R. norvegicus (6 + 2 from
ParkinsonsUK-UCL), D. melanogaster (2), C. elegans (1: ima-3),
A. thaliana (2: IMPA1, IMPA2). Total ~28 manual/experimental
annotations across ~25 distinct gene products. - GO branches: MF only. The replacement GO:0140142 sits under
GO:0005215 transporter activityrather thanGO:0005488 binding,
which is the explicit semantic shift driving go-ontology#31419
(binding-without-transport is no longer appropriate when the protein
actually carries the cargo through the NPC). - Type of fix: terminological + per-annotation triage. The bulk
(importins / karyopherins / exportins) move cleanly to GO:0140142.
The exceptions are: - Nucleoporins (Nup58, Nup98, Nup153, Nup214) — these are NPC
structural components, not carriers. The annotation likely came
from interaction assays with karyopherins / FG-repeat–binding,
and the right replacement is probably GO:0017056 structural
constituent of nuclear pore rather than GO:0140142. - NFKBIA / IκBα (PMID:1493333) — IκBα masks the NLS of NF-κB
p65/RelA; the "binding" assay measures IκBα binding to the NLS
region of p65, not nuclear-pore transit. The right replacement
is probably a transcription-factor-binding term or simply removal. - Su(fu) (PMID:24413177) — Su(fu) binds the NLS of Ci/Gli to
retain it in the cytoplasm (Hedgehog signaling). Again, not a
carrier; likely keep as a cargo-retention / NLS-masking MF or
remove. - NSR1 (Tier 3), Nolc1 (Tier 3), ETP1 (Tier 3),
Lbr (Tier 3), BRAP (Tier 4), Cabp1 (Tier 4) —
each needs literature triage to determine whether the original
assay supports a carrier role (→ GO:0140142) or a different
interaction role (→ alternative MF or remove). Tier assignments
are listed in the "Candidate genes for initial review" section
below; the diagnostic clusters are nucleolar cargo recognition
(NSR1, Nolc1), nuclear-envelope / membrane tethering (Lbr), and
cytoplasmic NLS-masking / retention (BRAP, ETP1, Cabp1). - Special case (FYPO dependency): when GO:0008139 is obsoleted,
FYPO:0007070's UbergraphImplementation needs to be updated upstream;
no action required from this repo.
Candidate genes for initial review
Verify each with just fetch-gene <organism> <gene> before starting.
None are currently in genes/.
Tier 1 — canonical karyopherins with multiple high-quality IDA annotations
- KPNA2 (human, UniProt P52292) — importin-α1; two independent
IDA annotations (PMID:17324944, PMID:28991411) plus extensive IBA
fanout. Canonical NLS-recognition receptor; clean GO:0140142
replacement. Good entry point for the importin-α family. - KPNA4 (human, UniProt O00629) — importin-α3; two
IDA annotations (PMID:20818336, PMID:38512451). Pair naturally
with KPNA2 review. - KPNB1 (human, UniProt Q14974) — importin-β1; PINC TAS
annotation (PMID:7627554). Textbook importin-β / RanGTP-cycle
nuclear import receptor; clean carrier-activity case and the
anchor for all KPNA/KPNB IBA propagations. - IPO4 (human, UniProt Q8TEX9) — importin-4 / RanBP4; IDA
PMID:17682055. Histone H3/H4 import; clean carrier case.
Tier 2 — yeast importins (PAINT seeds)
- PSE1 / KAP121 (S. cerevisiae, UniProt P32337) — IDA
PMID:11694505. Spo1 / pheromone-response NLS receptor. - KAP104 (S. cerevisiae, UniProt P38217) — IDA PMID:9488461.
hnRNP NLS receptor; the founding β-karyopherin for mRNA-binding
protein import. - KAP123 (S. cerevisiae, UniProt P40069) — IDA PMID:11694505.
Ribosomal protein import; pairs with PSE1. - MTR10 / KAP111 (S. cerevisiae, UniProt Q99189) — IDA
PMID:9545233. mRNA-binding protein import receptor. - KAP120 (S. cerevisiae, UniProt Q02932) — IDA PMID:20219973.
β-karyopherin; ribosomal-protein / Rpf1 import receptor. Clean
carrier-activity case; rounds out the yeast importin block.
Tier 3 — non-importin annotations that need triage
- NFKBIA / IκBα (human, UniProt P25963) — IPI PMID:1493333.
Diagnostic case: the GO:0008139 annotation reflects NLS-masking,
not NLS-carrying. The right call may be REMOVE or MODIFY to a
transcription-factor-binding term. This is the most interesting
review of the set. - Su(fu) (D. melanogaster, UniProt Q9VG38) — IPI
PMID:24413177. NLS-masking on Ci/Gli; similar triage to NFKBIA. - Nup98 (R. norvegicus, UniProt P49793), Nup153
(P49791), Nup214 (D4ACK1), Nup58 (P70581) — all
nucleoporins from PMID:7878057 (Radu et al. 1995) / PMID:8707840.
Annotation reflects FG-repeat binding to importins (transit
interaction), not NLS-binding for transport. Likely MODIFY to
GO:0017056 structural constituent of nuclear pore or removal. - NSR1 (S. cerevisiae, UniProt P27476) — IDA PMID:1706724.
Nucleolar SSB protein; NLS-binding assay reflects nucleolar
cargo-recognition rather than nucleocytoplasmic transit. Triage
needed — likely MODIFY to a nucleolar / cargo-binding MF rather
than GO:0140142. - ETP1 (S. cerevisiae, UniProt P38748) — IDA PMID:9497340.
Same primary reference as human BRAP (Tier 4) and similar
cytoplasmic NLS-binding context; triage needed to determine
whether ETP1 acts as a carrier or as a retention factor. - Lbr (R. norvegicus, UniProt O08984) — IPI PMID:8486604.
Lamin B receptor; inner-nuclear-membrane protein whose NLS
interaction reflects nuclear-envelope tethering of cargos
rather than nucleocytoplasmic transport. Likely MODIFY to a
nuclear-envelope-binding MF or removal. - Nolc1 (R. norvegicus, UniProt P41777) — IDA PMID:1623516.
Nucleolar/nucleolar-organizing-region phosphoprotein (NOPP140);
NLS-binding assay likely reflects nucleolar cargo recognition.
Triage in parallel with NSR1.
Tier 4 — disease-relevant / outlier annotations
- BRAP (human, UniProt Q7Z569) — IDA PMID:9497340. BRCA1-
associated protein; cytoplasmic retention factor for NLS-bearing
cargos. Triage needed (cargo-retention, not carrier). - Cabp1 (R. norvegicus, UniProt O88751) — IDA PMID:18303947
(UniProt + ParkinsonsUK-UCL). Calcium-binding protein 1; the
NLS-binding assertion is unusual for a Ca²⁺-binding signalling
protein and warrants a careful triage of the underlying
immunoprecipitation / pulldown evidence. - IMPA1 (UniProt Q96321) and IMPA2 (UniProt F4JL11)
— A. thaliana importin-α homologs; both IMP PMID:37676567.
Pair the two together; useful plant-side coverage.
Proposed approach
- No urgent action. The ontology ticket (go-ontology#31419) is
CLOSED — the conceptual decision is settled — but the per-annotation
remapping in go-annotation#6435 is still in progress. The PomBase
entry (cut15) is the only one already DONE. Reviews can proceed
immediately using the live GO:0140142 term as the proposed
replacement; the formal obsoletion of GO:0008139 will follow the
per-annotation triage. - Begin with KPNA2 + KPNA4 (paired). These are the cleanest cases
for the GO:0140142 replacement and the IDA evidence is strong and
recent. KPNA2's two independent IDAs from different groups make
it an especially solid template. - Add KPNB1 next. The canonical importin-β; anchors the IBA
fanout for the broader karyopherin family. - Tackle a Tier-3 diagnostic case (NFKBIA or Su(fu)) early to
stress-test the per-annotation triage logic. These are the
annotations where the carrier-vs-masking distinction matters most
and where a straightMODIFYto GO:0140142 would be wrong. - Yeast importin block (PSE1 / KAP104 / KAP123 / MTR10 / KAP120)
as one project. Shared literature and shared cargo classes
(ribosomal protein import, mRNA-binding protein import) make a
paired review efficient. Run the yeast triage cases (NSR1, ETP1)
alongside or immediately after, since they share publications and
curation context with the importin block. - Nucleoporin block (Nup58 / Nup98 / Nup153 / Nup214) —
probably one review per protein, with consistent MODIFY → GO:0017056
recommendations and a shared rationale citing Radu et al. 1995
(PMID:7878057) as the original annotation source. - Cross-reference with
- [[MITOCHONDRION_TARGETING_SEQUENCE_BINDING_OBSOLETION]] (same
parent refactor wave) - [[PEROXISOME_TARGETING_SIGNAL_OBSOLETION]] (same parent)
- Any future nuclear-pore / nucleocytoplasmic transport projects.
Priority
Low-medium. The biology is canonical (nuclear-import machinery is
textbook), the upstream ontology decision is settled, and no existing
reviews in this repo are blocked. This is opportunistic — KPNA/KPNB
family is a major unreviewed area, and the triage cases (NFKBIA, Su(fu),
nucleoporins) make for instructive diagnostic reviews of the
carrier-vs-binding distinction. PINC's 5 TAS annotations (1990s-era
reviews) are also good candidates for evidence-code modernization.
Status
- 2026-06-02 — Review follow-up: spot-checked Q96321 (IMPA1_ARATH) and
F4JL11 against UniProt REST, added an explanatory note for the
MGI/Q7Z569 (human BRAP) curation pattern, added KAP120 to Tier 2,
and added explicit tier assignments for NSR1 / ETP1 / Lbr / Nolc1 /
Cabp1 in Tiers 3 and 4. No biological conclusions changed. - 2026-06-01 — Project file created. Tracking upstream issue
geneontology/go-annotation#6435 (opened 2026-05-27, updated 2026-06-01).
Upstream ontology ticket geneontology/go-ontology#31419 is CLOSED
(decision settled; per-annotation triage in progress). Verified
GO:0008139 still live in OLS (isObsolete: false) and GO:0140142
(nucleocytoplasmic carrier activity) live and ready as replacement.
Verified the annotation source tally via QuickGO REST: UniProt 10,
SGD 7, RGD 6 manual + 5 ortholog-projection, PINC 5, FlyBase 2,
ParkinsonsUK-UCL 2, MGI 1, PomBase 1 (DONE). Total bulk fanout is
~18k IEA/IBA entries that follow automatically. One InterPro2GO
mapping (IPR024882, Nucleoporin p58/p45/NUP49) flagged for
redirection. No UniRule/Keywords mappings. No gene reviews started
yet in this repo; none of the ~25 affected gene products are present
undergenes/.