Nudt2 (mouse, P56380) review notes

Summary of evidence

• Mouse Nudt2 (Apah1) is the PTHR21340:SF0 asymmetrical Ap4A hydrolase, 147 aa, Nudix box
  at 43-64, Tetra_PHTase signature (IPR003565). Orthologue of human NUDT2 and worm ndx-4.
• No direct Ap4A assay on the mouse protein; the activity is transferred from pig P50584
  and worm Q9U2M7. Worm ndx-4 kinetics:
  PMID:11738085
• In cells, the mammalian Nudt2 product turns over Ap4A in activated mast cells, affecting
  MITF/USF2 target genes (abstract does not state species/cell lines):
  PMID:18644867
• Recombinant mouse Nudt2 decaps dpCoA- and FAD-capped RNA in vitro (catalytic EE-QQ
  mutant inactive), no deNADding; loss of Nudt2 in cells did not alter FAD-capped RNA:
  PMID:32432673
  PMID:32432673
  (Note the abstract lists six names for "seven" proteins; Figure 3C text adds Nudt12.)
• Mitochondrion HDA from MitoCarta proteomics; Nudt2 not discussed in the text
  PMID:18614015
• Family-wide in vitro PRPP pyrophosphatase activity, minor for Ap4A hydrolases (human
  enzyme kcat 0.057 s-1) PMID:12370170; mouse has no PRPP annotation, so not used.

Curation decisions (consistent with genes/worm/ndx-4)

• GO:0004081 (IBA, IEA, 2x ISS): ACCEPT.
• GO:0008796 IEA: ACCEPT (broader parent).
• GO:0016787 hydrolase IEA: MODIFY -> GO:0004081.
• GO:0006167 AMP / GO:0006754 ATP biosynthetic process (IBA from PTN000482012):
  MARK_AS_OVER_ANNOTATED; product-based, node seeded solely by worm ndx-4 IDA rows that
  were themselves marked over-annotated.
• GO:0006915 apoptotic process ISS (from worm, citing the structure paper PMID:11937063):
  REMOVE; transfer of a speculative statement whose worm TAS source was removed.
• GO:0005739 mitochondrion HDA: KEEP_AS_NON_CORE (experimental, cannot check supplement;
  human NUDT2 independently has a mitochondrial matrix annotation).
• NEW GO:0015967 diadenosine tetraphosphate catabolic process (ISS, PMID:18644867):
  the enzyme performs the hydrolytic step; comparator ndx-4 carries it by IDA.
• RNA cap decapping: no GO terms exist for FAD-cap/dpCoA-cap decapping (GO:0110155 is
  NAD-cap only, and Nudt2 lacks deNADding). In vitro only and without a cellular effect,
  so no NEW term proposed; raised as a suggested question.

PAINT notes

PTN000482012 IBDs for GO:0006167 and GO:0006754 cite only WB:WBGene00003581 (ndx-4).
These product-based process terms propagate to all SF0 members (mouse, human, ...); the
appropriate node-level process would be GO:0015967.

Additional literature (found via deep research, verified against cached abstracts)

• Mouse Nudt2 decaps m7G- and G-capped RNA in vitro, producing m7GMP and m7GDP:
  PMID:23353937
• Human NUDT2 knockout raises Ap4A 175-fold:
  PMID:27144453
• Ap4A is a 5' RNA cap; NUDT2 and DXO cleave Ap4A-RNA in vitro:
  PMID:37934413
• Human biallelic NUDT2 variants cause a neurodevelopmental disorder; decapping implicated:
  PMID:38141063
  The deep research report reads this as a NUDT2 separation-of-function variant; the
  abstract does not say which Ap4A hydrolase was used, so that interpretation is not adopted.

Decapping GO terms considered and not proposed: GO:0140933 (m7GDP-releasing) and
GO:0140932 (m7GMP-releasing) each capture only one of Nudt2's two products; the evidence
for mouse is in vitro, and the physiological cap substrate (m7G vs Ap4A) is unresolved.
Raised as a suggested question.

Deep research status

OpenScientist completed 2026-10-08 (~14 min): Nudt2-deep-research-openscientist.md.
Most claims are orthologue-based (Drosophila Apf nuclear localization PMID:17344088,
human structure PMID:23384440, LysRS-Ap4A-HINT1-MITF axis PMID:14975237); none
change the curation decisions. It confirms no Nudt2 knockout mouse phenotype was found.

2026-10-12 Ortholog/family audit

GOA refetched (no new rows). Audited against human NUDT2 (COMPLETE) and worm ndx-4; PANTHER family PTHR21340:SF0 (node PTN000482012) confirmed from UniProt.

Family/ortholog consistency gap found and fixed. The mouse review carried only the Ap4A-hydrolase function, but human NUDT2 also carries RNA decapping (GO:0110154) and mRNA 5'-triphosphate monophosphatase activity (GO:0140818) as core, and the mouse protein has been assayed directly for these:
- PMID:32432673 — recombinant mouse Nudt2, dpCoA/FAD/m7G caps; EE-QQ mutant inactive.
- PMID:23353937 — mouse m7G decapping (mixed m7GMP/m7GDP products).
- PMID:34824277 — previously MISSED by this review and by the OpenScientist deep-research report. This is a Nudt2-KNOCKOUT MOUSE paper: "Homozygous knockout mice were viable, bred with expected Mendelian ratios"; bone-marrow cells show 10-30x more growth of 5'-PPP-RNA viruses. Enzymology shows "NUDT2 sequentially releases two phosphates" from 5'-PPP RNA to a monophosphate end for XRN1.

Changes: added GO:0110154 (NEW, IDA, non-core relative to Ap4A) and GO:0140818 (NEW, ISS — enzymology species unstated but knockout is mouse), added a second core_function (mRNA 5'-triphosphate monophosphatase / RNA decapping), added PMID:34824277 reference, expanded description, flipped the openscientist "no knockout mouse" finding to finding_status OVERTURNED superseded_by PMID:34824277, and added suggested_questions on virus-defence process and GO:0140818 mRNA-restriction. Ap4A core unchanged.