Pias1 (mouse, UniProt O88907) - curation notes

Sources and status

• UniProt record Pias1-uniprot.txt (651 aa; PIAS family; SAP, PINIT, SP-RING/Znf-MIZ, SIM).
• Deep research: Pias1-deep-research-openscientist.md (not edited). Claims checked against
  cached primary sources before use (see "Integration of openscientist report").
• Cached publications for every PMID in the GOA set; full text available for PMID:16127449,
  PMID:16522640, PMID:22406621, PMID:22539995, PMID:18832723, PMID:23118920, PMID:24061474,
  PMID:34459572. Abstract-only: PMID:16600910, PMID:14611647, PMID:17187077, PMID:15123625,
  PMID:15229330, PMID:15507114, PMID:16816390, PMID:9724754.
• Human ortholog review genes/human/PIAS1/ used for consistency; decisions mirror it unless
  mouse evidence differs. Human-derived papers reused here (already cached): PMID:9724754,
  PMID:12764129, PMID:15311277, PMID:15657437, PMID:17540171, PMID:20016603, PMID:27099310,
  PMID:36050397.

Synthesis

1. SP-RING SUMO E3 ligase (core)

• UniProt: [file:mouse/Pias1/Pias1-uniprot.txt "Functions as an E3-type small ubiquitin-like modifier (SUMO)"].
• C/EBPbeta in 3T3-L1 adipogenesis PMID:24061474;
  catalytic activity required PMID:24061474.
• GATA4 in intestinal cells PMID:22539995.
• PML and PML-RARA PMID:22406621.
• FOXA2 PMID:23118920.
• PPARgamma PMID:15123625;
  in macrophages PMID:16127449.
• Nr2c1/Tr2 (UniProt SUBUNIT, PMID:17187077) [file:mouse/Pias1/Pias1-uniprot.txt "Interacts with NR2C1; the interaction promotes its"].

2. Inhibitor of activated transcription factors (core)

Mouse genetics is the physiological foundation of this function:
- Pias1-/- mice: PMID:15311277.
- NF-kB: PMID:15657437; Pias1-/- cells show
enhanced p65 promoter occupancy and null mice elevated proinflammatory cytokines.
- STAT1 inhibition does not need STAT1 sumoylation PMID:12764129.
- Switched on by IKKalpha phosphorylation at Ser90, which requires PIAS1 ligase activity PMID:17540171.
- PPARgamma transrepression of NF-kB targets in macrophages requires PIAS1 (PMID:16127449, PMID:18832723) -
an indirect, SUMO-dependent route to inflammatory gene repression.

3. Context-dependent coactivation / cofactor roles (non-core)

• GATA4 coactivation is ligase-independent PMID:22539995.
• Msx1: PIAS1 tethers Msx1 to the nuclear periphery and confers DNA-binding specificity
  PMID:16600910.
• TBP binding via a conserved 39-aa C-terminal region PMID:16522640.

4. DNA damage (from human; ISO)

• PMID:36050397
• PMID:20016603

5. Localization

Nucleus/nucleoplasm, nuclear speckles (ISS), PML bodies PMID:27099310;
partial synaptic co-localization in cultured hippocampal neurons
PMID:34459572.

Judgements on specific rows

• Protein binding (6 IPI): MODIFY Msx1 -> DNA-binding transcription factor binding; PPARgamma ->
  peroxisome proliferator activated receptor binding; Nr2c1/Tr2 -> nuclear receptor binding (UniProt
  states the interaction promotes Tr2 sumoylation); TBP -> TBP-class protein binding. REMOVE Sufu (Y2H
  hit, not confirmed in the abstract) and PML (substrate recognition already captured by SUMO ligase
  activity and protein sumoylation).
• fat cell differentiation (IDA PMID:24061474) -> MODIFY to negative regulation of fat cell
  differentiation: overexpression inhibits and knockdown promotes adipogenesis.
• positive regulation of protein localization to cell periphery (IDA PMID:16600910) -> MODIFY to
  protein localization to nuclear periphery (GO:1990139): the paper concerns the nuclear periphery, not
  the cell periphery (plasma membrane region). The human IEA row projected from this one was
  MARK_AS_OVER_ANNOTATED in the human review; that remains defensible but the root cause is this
  term choice.
• ubiquitin protein ligase activity (IEA, EC 2.3.2.27 mapping) -> REMOVE; UniProt uses the RING-type
  EC for SUMO E3s, but PIAS1 is a SUMO, not ubiquitin, ligase.
• transcription corepressor activity (ISO) -> MODIFY to transcription regulator inhibitor activity,
  JAK-STAT pathway (ISO) -> MODIFY to negative regulation, positive regulation of protein sumoylation ->
  MODIFY to protein sumoylation (same as human).
• Knockout/knockdown phenotypes (visual learning, spermatogenesis, G1/S, apoptosis, proliferation,
  protein-DNA complex assembly): PIAS1 does not execute these processes; they are downstream of
  transcription-factor sumoylation/inhibition -> MARK_AS_OVER_ANNOTATED (as human). Smooth muscle
  differentiation, positive regulation of transcription, synaptic locations -> KEEP_AS_NON_CORE.
• The innate-immunity phenotype of Pias1-/- mice (PMID:15311277) is captured mechanistically by
  negative regulation of JAK-STAT signalling and NF-kB signalling; no immune-process NEW term proposed.
• NEW: negative regulation of canonical NF-kappaB signal transduction (GO:0043124), IMP from Pias1-/-
  cells/mice (PMID:15657437). Participation: PIAS1 itself binds p65 and blocks its DNA binding.
  Comparator (QuickGO 2026-10, mouse, exact term): Nfkbie, Nfkbid, Tnfaip3 and Hdac1 carry GO:0043124.
  Mirrors the human NEW.

Integration of openscientist report

Verified against cached sources: STAT1 promoter-recruitment blockade (PMID:15311277), p65 DNA-binding
blockade (PMID:15657437), SUMO-independent STAT1 inhibition (PMID:12764129), Ser90/IKKalpha
(PMID:17540171), PML-NB constituent (PMID:27099310), C/EBPbeta substrate (PMID:24061474).
Not verified (not cached) and not used for annotations: PNKP, Hes-1, AICD substrates, MK2 Ser522,
GSK3beta/HECTD2 degradation, GBP clone (PMID:9177271). Note the report omits that PIAS1 is NOT the
STAT1 E3 PMID:12764129.

Open questions

• Which inflammatory phenotypes of Pias1-/- mice depend on E3 activity vs binding-based inhibition?
• Is PIAS1 tethering of transcription factors (Msx1) to the nuclear periphery a general mechanism?

2026-10-12 Ortholog/family audit

• GOA refreshed: no change; all 94 GOA rows covered; NEW GO:0043124 (PMID:15657437) retained.
• Compared with genes/human/PIAS1 (DRAFT) and family members genes/worm/gei-17, genes/yeast/SIZ1, genes/ARATH/SIZ1 (no PIAS2/3/4 or other Pias reviews exist). All use SUMO ligase activity (GO:0061665) as core MF with protein sumoylation; SUMO transferase activity, chromatin and nucleoplasm IBAs are accepted throughout. Mouse and human PIAS1 agree on every shared term, including MODIFY of transcription corepressor activity to transcription regulator inhibitor activity, JAK-STAT to its negative regulation, positive regulation of protein sumoylation to protein sumoylation, and fat cell differentiation to negative regulation of fat cell differentiation.
• Human PIAS1 GOA file is older than the mouse ISO rows: mouse carries ISO GO:0000724 and GO:0000729 from human O75925 that are absent from genes/human/PIAS1/PIAS1-goa.tsv; the human review should be refreshed with just fetch-gene human PIAS1 (not done here; outside assignment).
• No changes made to the mouse review.