PIAS1 (human, UniProt O75925) - curation notes

Deep research status

Deep research was attempted with several providers: falcon returned HTTP 402, perplexity
was unavailable, and openai returned HTTP 401. The openscientist provider succeeded and
produced PIAS1-deep-research-openscientist.md (not edited). Its key claims were checked
against cached primary sources before use (see "Integration of openscientist report"
below). The synthesis below is my own, built from the UniProt record
(PIAS1-uniprot.txt), the cached publications for every PMID in the GOA annotation set,
and additional papers fetched with just fetch-pmid (PMID:11583632, PMID:11867732,
PMID:15311277, PMID:15657437, PMID:20016603, PMID:12764129, PMID:17540171, PMID:27099310,
PMID:32348746).

Domain architecture (UniProt)

• SAP domain (aa 11-45), with an LXXLL coregulator motif (aa 19-23) inside it
• PINIT domain (aa 124-288)
• SP-RING-type zinc finger (aa 320-405), the E3 catalytic module that binds UBE2I/UBC9;
  C351 mutation abolishes UBE2I binding [file:human/PIAS1/PIAS1-uniprot.txt "C->A,S: Loss of UBE2I-binding; almost complete loss"]
• SUMO1-binding region / SIM (aa 462-473)
• Ser/Thr-rich C-terminus with disordered segments and N-T-S-L repeats
• Two predicted NLSs; family: PIAS family (PIAS1-4 in human; Siz1/Siz2 in yeast)

Synthesis

1. SP-RING-type SUMO E3 ligase

PIAS1 was identified as a SUMO-1-binding protein that also binds UBC9 and p53 and
catalyses p53 sumoylation via its RING-like domain PMID:11583632.
Independently, PIAS1 and PIASxbeta were shown to act as E3-like ligases for p53 and
c-Jun PMID:11867732.
The E3 activity of PIAS proteins resides in the SP-RING PMID:20972456.

Documented substrates (selection, from cached papers):
- Sp3 PMID:12356736; recombinant GST-PIAS1 drives near-complete conjugation in vitro.
- Mdm2 PMID:12393906.
- ZNF76 PMID:15280358.
- HIC1 PMID:17283066.
- Nkx2.5 PMID:18579533.
- MTA1 PMID:21965678.
- Blimp-1/PRDM1 PMID:22555612.
- FLASH/CASP8AP2 (PMID:21338522; RING-finger mutant fails to enhance FLASH activity).
- MRE11, the best-characterised recent substrate PMID:36050397; in vitro reconstitution with purified MBP-PIAS1 enhances SUMO2 conjugation.
- PIAS1 is also routinely used as a positive-control SUMO E3 (e.g. PMID:27068747).
- Reactome lists many further PIAS1 SUMOylation reactions (BRCA1, SP3, MTA1, DDX5, FOXL2, SAFB, NRIP1, HIC1, MBD1, AR, ESR1, NR3C2, NR5A1/2, XRCC4, SATB1/2, THRB, CASP8AP2, L3MBTL2).

2. Transcriptional coregulator / inhibitor of activated transcription factors

• STAT1: PIAS1 was discovered as a specific inhibitor of STAT1 PMID:9724754. The C-terminal region (aa 392-541) binds the STAT1 N-terminal domain and only dimeric, tyrosine-phosphorylated STAT1 PMID:10805787. In Pias1-/- mice a subset of IFN-inducible genes is derepressed PMID:15311277.
• NF-kB: PMID:15657437; Pias1-null cells show increased p65 promoter occupancy and mice show elevated proinflammatory cytokines.
• PIAS1 can also act positively: e.g. it enhances c-Myb coactivation by FLASH (PMID:21338522), and relieves ZNF76-mediated repression of p53 targets by sumoylating ZNF76 (PMID:15280358). The mechanism of action (inhibition vs activation) is context- and substrate-dependent, as UniProt notes.
• The SAP domain binds p53 and A/T-rich DNA PMID:15133049; this is the basis for the "cis-regulatory region binding" ISS annotation (from mouse Pias1 + Msx1 data), but sequence-specific DNA binding as a function in vivo is not established for human PIAS1.

3. DNA damage response

• PIAS1 and PIAS4 are recruited to DSBs via their SAP domains and are needed for SUMO accrual, BRCA1/53BP1/RNF168 retention, DSB repair and IR resistance PMID:20016603.
• PIAS1 sumoylates MRE11 on chromatin to stabilise it and promote end resection PMID:36050397.

4. Localization

Nuclear; nuclear speckles and PML bodies (UniProt; PMID:27068747). Cytoskeletal localization is a partial redistribution under CSRP2 overexpression (UniProt note), not a primary location. Mouse SynGO-based synaptic cytosol annotations are peripheral.

Judgements on problematic annotations

• 55 GO:0005515 protein binding IPI rows: 42 come from a single Y2H neurodegeneration
  interactome (PMID:32814053) plus other Y2H/high-throughput screens (PMID:23275563,
  PMID:21911577, PMID:16154161) -> REMOVE (uninformative; HTT interaction was not
  confirmed by LUMIER in PMID:23275563). Rows from papers that show PIAS1 acting on a
  transcription factor or coregulator substrate -> MODIFY to DNA-binding transcription
  factor binding / p53 binding / transcription coregulator binding / SUMO binding.
• "transcription corepressor activity" (TAS, PMID:10805787) -> MODIFY to transcription
  regulator inhibitor activity: PIAS1 inhibits STAT1 by blocking its DNA binding, not by
  recruiting repressive machinery.
• "cell surface receptor signaling pathway via JAK-STAT" -> MODIFY to negative regulation.
• "positive regulation of protein sumoylation" -> MODIFY to protein sumoylation (PIAS1 is
  the E3 itself, so it participates directly).
• Rat/mouse Ensembl-Compara IEAs for visual learning, spermatogenesis, G1/S transition,
  apoptosis, proliferation, protein-DNA complex assembly: physiological outcomes of
  transcription-factor sumoylation, not core functions -> MARK_AS_OVER_ANNOTATED or
  KEEP_AS_NON_CORE.
• NEW: negative regulation of canonical NF-kappaB signal transduction (GO:0043124),
  passes participation (PIAS1 itself binds p65 and blocks its DNA binding) and comparator
  (NFKBIA, TNFAIP3 and PIAS4 carry the term in QuickGO, 2026-10).

Integration of openscientist report

Verified against cached primary sources:
- SUMO-independent STAT1 inhibition PMID:12764129. Notably this paper also shows that PIAS1 is not the STAT1 E3 PMID:12764129, which the report does not emphasise.
- Inflammation-induced switch PMID:17540171; Ser90 phosphorylation is required for repression and for TNF-induced promoter association, and itself requires PIAS1 SUMO ligase activity.
- PML nuclear bodies PMID:27099310; PIAS1 enhances SUMO1 accumulation in domains containing infecting HSV-1 genomes but is not essential for PML-NB formation.
- SIM2 PMID:32348746, supporting the SUMO binding MODIFY for the SUMO5 IPI row.
- STAT1/p65 blockade and DSB role match PMID:9724754, PMID:10805787, PMID:15657437, PMID:15311277 and PMID:20016603 (already used).

Not verified (not cached) and therefore not used for annotations: substrate claims for
Smad4, PPARG, HMGN2, mGluR8b and EBNA1, AR ChIP-seq coregulation (PMID:25552417,
PMID:26219822), and disease-model papers. AR coregulation is consistent with the existing
KEEP_AS_NON_CORE call on positive regulation of DNA-templated transcription.

Effect on decisions: no action changed. The report reinforced the MODIFY of
"transcription corepressor activity" to "transcription regulator inhibitor activity"
(the inhibition is SUMO-independent, binding-based), the PML body ACCEPTs, the SUMO
binding MODIFY, and the NEW NF-kB annotation (now also supported by PMID:17540171).

Open questions

• Is PIAS1 inhibition of STAT1/p65 DNA binding dependent on its E3 activity? (Evidence
  suggests not for STAT1; PMID:12356736 discussion notes this is unclear.)
• Extent of redundancy with PIAS4 in the DDR and SUMO paralog selectivity in vivo.

Literature review integration (2026-10-04)

• Palvimo 2007 (PMID:18031232, abstract only) added as family-level support for the GO:0140416 IBA ACCEPT
  PMID:18031232
  and for the transcription-regulator-inhibitor core function PMID:18031232.
  This bears on the open question above: E3-independent co-regulator activity is a recognised PIAS-family property.
• No actions changed.

Cross-gene briefing for GO editors and PAINT curators: https://claude.ai/artifact/4MLfbbbWWnLchDvspwdPuM