PRDX4

Summary: cytosol localization is supported for a smaller PRDX4 pool, including the cytoplasmic fraction implicated in NF-kappaB redox modulation.

Reason: Although the endoplasmic reticulum is the dominant core location, UniProt and experimental literature support a cytoplasmic fraction. The term is therefore valid, with ER retained as the primary localization.

Summary: response to oxidative stress is supported by PRDX4 peroxide-reducing activity and its role in cellular redox protection.

Reason: PRDX4 directly detoxifies hydroperoxides through the thioredoxin system, so these redox and peroxide catabolic process annotations are appropriate biological-process summaries.

Summary: thioredoxin peroxidase activity accurately captures PRDX4 catalysis as a thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydroperoxides.

Reason: This is the core molecular function of PRDX4 and is supported by both the original thioredoxin peroxidase study and structural/catalytic analysis.

Summary: hydrogen peroxide catabolic process is supported by PRDX4 peroxide-reducing activity and its role in cellular redox protection.

Reason: PRDX4 directly detoxifies hydroperoxides through the thioredoxin system, so these redox and peroxide catabolic process annotations are appropriate biological-process summaries.

Summary: cell redox homeostasis is supported by PRDX4 peroxide-reducing activity and its role in cellular redox protection.

Reason: PRDX4 directly detoxifies hydroperoxides through the thioredoxin system, so these redox and peroxide catabolic process annotations are appropriate biological-process summaries.

Summary: Endoplasmic reticulum is the core location of PRDX4. Endogenous PRDX4 is cotranslationally translocated into, and retained within, the ER of human cells, where it removes the hydrogen peroxide made by the ER oxidase Ero1.

Reason: ER residence is the most informative location for PRDX4, the only signal-peptide-bearing human peroxiredoxin. ORGANELLES check (2026-11-05): the PAINT IBD at PTN000841180 (PTHR10681) is seeded by fly Jafrac2 (FBgn0040308), mouse and rat Prdx4 and human PRDX4 itself (an expected seed, not circular), so it places ER residence at the PRDX4 clade. The human claim is direct: Tavender et al. (PMID:18052930, full text) show cleavage of the signal peptide, proteinase K protection of mature PRDX4 in calnexin-containing organelle membranes, co-staining with an anti-KDEL ER marker, ER retention of the endogenous protein for five hours after cycloheximide, and no secretion. The is_active_in qualifier is supported: PRDX4 metabolises H2O2 produced by Ero1 inside the ER and protects cells against ER oxidative stress (PMID:20627953, abstract). The row stays at the root; the lumenal sub-compartment is added as a separate NEW GO:0005788 row.

Summary: cellular oxidant detoxification is supported by PRDX4 peroxide-reducing activity and its role in cellular redox protection.

Reason: PRDX4 directly detoxifies hydroperoxides through the thioredoxin system, so these redox and peroxide catabolic process annotations are appropriate biological-process summaries.

Summary: peroxidase activity is compatible with PRDX4 biology but is a broad parent or less-informative activity compared with the specific thioredoxin-dependent peroxiredoxin annotations already present.

Reason: The precise MF terms GO:0140824/GO:0051920/GO:0008379 better represent PRDX4. Broad antioxidant/peroxidase/oxidoreductase terms add little specificity.

Summary: cytoplasm localization is supported for a smaller PRDX4 pool, including the cytoplasmic fraction implicated in NF-kappaB redox modulation.

Reason: Although the endoplasmic reticulum is the dominant core location, UniProt and experimental literature support a cytoplasmic fraction. The term is therefore valid, with ER retained as the primary localization.

Summary: Endoplasmic reticulum is the core location of PRDX4. Endogenous PRDX4 is cotranslationally translocated into, and retained within, the ER of human cells.

Reason: ER residence is the most informative location for PRDX4. ORGANELLES check (2026-11-05): this combined-source row (GO_REF:0000120) rests on UniProt SL-0095 plus the mouse ortholog O08807, and the human UniProt ER line is curated from PMID:18052930 (ECO:0000269), whose full text shows signal-peptide cleavage, proteinase K protection inside calnexin-containing membranes, KDEL co-staining and retention of endogenous PRDX4 without secretion. The organelle claim holds, so the row is kept at the root; the lumenal sub-compartment is a separate NEW GO:0005788 row.

Summary: antioxidant activity is compatible with PRDX4 biology but is a broad parent or less-informative activity compared with the specific thioredoxin-dependent peroxiredoxin annotations already present.

Reason: The precise MF terms GO:0140824/GO:0051920/GO:0008379 better represent PRDX4. Broad antioxidant/peroxidase/oxidoreductase terms add little specificity.

Summary: oxidoreductase activity is compatible with PRDX4 biology but is a broad parent or less-informative activity compared with the specific thioredoxin-dependent peroxiredoxin annotations already present.

Reason: The precise MF terms GO:0140824/GO:0051920/GO:0008379 better represent PRDX4. Broad antioxidant/peroxidase/oxidoreductase terms add little specificity.

Summary: peroxiredoxin activity accurately captures PRDX4 catalysis as a thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydroperoxides.

Reason: This is the core molecular function of PRDX4 and is supported by both the original thioredoxin peroxidase study and structural/catalytic analysis.

Summary: thioredoxin-dependent peroxiredoxin activity accurately captures PRDX4 catalysis as a thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydroperoxides.

Reason: This is the core molecular function of PRDX4 and is supported by both the original thioredoxin peroxidase study and structural/catalytic analysis.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: Generic protein binding from interactome evidence does not describe the specific PRDX4 molecular function.

Reason: PRDX4 has biologically relevant partners and oligomerization, but GO:0005515 is too vague. Specific terms for peroxiredoxin activity and identical protein binding capture the supported function better.

Summary: cytosol localization is supported for a smaller PRDX4 pool, including the cytoplasmic fraction implicated in NF-kappaB redox modulation.

Reason: Although the endoplasmic reticulum is the dominant core location, UniProt and experimental literature support a cytoplasmic fraction. The term is therefore valid, with ER retained as the primary localization.

Summary: Identical protein binding is supported by PRDX4 homodimerization and decamer formation, which are part of its 2-Cys peroxiredoxin catalytic assembly.

Reason: Unlike generic protein binding, identical protein binding is mechanistically informative for PRDX4 because catalysis uses a dimeric interface and oxidized PRDX4 forms disulfide-linked homodimers/decamers.

Summary: Endoplasmic reticulum is the core location of PRDX4; Human Protein Atlas immunofluorescence detects it in the ER.

Reason: ER residence is the most informative location for PRDX4. ORGANELLES check (2026-11-05): the HPA immunofluorescence assay (GO_REF:0000052) cannot resolve lumen from membrane, so under rule 2 the root row is accepted as what the experiment shows. It agrees with the independent biochemistry of PMID:18052930 (protease protection inside calnexin-containing membranes, KDEL co-staining, retention of endogenous PRDX4). The lumenal sub-compartment is a separate NEW GO:0005788 row.

Summary: Proposed sub-compartment. PRDX4 is a soluble protein with a cleaved N-terminal signal peptide that is fully translocated into, and retained within, the ER, which places it in the ER lumen; the existing annotations stop at the organelle.

Reason: Added under the ORGANELLES policy (rule 4, 2026-11-05), beside the three root GO:0005783 rows, which are kept. Three independent lines agree. (1) Topology: UniProt records an N-terminal signal peptide (1-37) whose cleavage after Gly-37 is shown experimentally, and the mature chain has no TM segment or membrane anchor, so after translocation it can only be lumenal. (2) A direct assay: in PMID:18052930 the mature protein co-fractionates with calnexin and, like the calnexin lumenal domain, is protected from proteinase K, and endogenous PRDX4 stays with ER markers for five hours after cycloheximide and is not secreted; PRDX4 lacks a KDEL-type motif, so retention does not rest on a sequence signal. (3) Function only possible on the lumenal side: PRDX4 metabolises H2O2 produced by Ero1, the lumenal oxidase of disulphide formation (PMID:20627953). Because the peroxidase activity itself is shown acting on Ero1-derived H2O2 there, core_functions names the ER lumen beside the root.

Summary: cytosol localization is supported for a smaller PRDX4 pool, including the cytoplasmic fraction implicated in NF-kappaB redox modulation.

Reason: Although the endoplasmic reticulum is the dominant core location, UniProt and experimental literature support a cytoplasmic fraction. The term is therefore valid, with ER retained as the primary localization.

Summary: The cited structural study supports PRDX4 peroxidase catalysis, oligomerization, and overoxidation sensitivity, but it does not establish molecular adaptor activity as a distinct molecular function.

Reason: The biological evidence should be captured with a catalytic peroxiredoxin term rather than adaptor or sequestering activity. The best replacement is the specific thioredoxin-dependent peroxiredoxin activity term already supported by the same catalytic mechanism.

Proposed replacements: thioredoxin-dependent peroxiredoxin activity

Summary: The cited structural study supports PRDX4 peroxidase catalysis, oligomerization, and overoxidation sensitivity, but it does not establish molecular sequestering activity as a distinct molecular function.

Reason: The biological evidence should be captured with a catalytic peroxiredoxin term rather than adaptor or sequestering activity. The best replacement is the specific thioredoxin-dependent peroxiredoxin activity term already supported by the same catalytic mechanism.

Proposed replacements: thioredoxin-dependent peroxiredoxin activity

Summary: extracellular region reflects secretory or extracellular detection/pathway context for PRDX4 rather than the main site of its curated peroxidase function.

Reason: PRDX4 is an ER/secretory-pathway peroxiredoxin, so extracellular or granule-lumen pathway placements can be retained as non-core context while ER remains the primary location.

Summary: extracellular region reflects secretory or extracellular detection/pathway context for PRDX4 rather than the main site of its curated peroxidase function.

Reason: PRDX4 is an ER/secretory-pathway peroxiredoxin, so extracellular or granule-lumen pathway placements can be retained as non-core context while ER remains the primary location.

Summary: secretory granule lumen reflects secretory or extracellular detection/pathway context for PRDX4 rather than the main site of its curated peroxidase function.

Reason: PRDX4 is an ER/secretory-pathway peroxiredoxin, so extracellular or granule-lumen pathway placements can be retained as non-core context while ER remains the primary location.

Summary: ficolin-1-rich granule lumen reflects secretory or extracellular detection/pathway context for PRDX4 rather than the main site of its curated peroxidase function.

Reason: PRDX4 is an ER/secretory-pathway peroxiredoxin, so extracellular or granule-lumen pathway placements can be retained as non-core context while ER remains the primary location.

Summary: nucleus comes from high-throughput proteomic detection and is not the main functional location of PRDX4.

Reason: Retain the observation as non-core because proteomic localization can reflect cargo or context-specific detection. It should not displace the ER/cytoplasmic peroxiredoxin localization.

Summary: Detected in an extracellular-vesicle proteome, but the detection does not establish that this protein is an EV constituent.

Reason: ER-lumen peroxiredoxin. Mainly resident in an intracellular compartment that MISEV2018 (PMID:30637094) lists as not enriched in small EVs of plasma-membrane/endosomal origin (category 4), and its own review keeps no experimental cell-surface or plasma-membrane pool; an exosome annotation from a bulk EV proteome is not supported. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: KEEP_AS_NON_CORE.)

Summary: PRDX4 modulates I-kappaB-alpha phosphorylation through redox regulation but is not the kinase that phosphorylates I-kappaB.

Reason: The evidence supports regulation of I-kappaB phosphorylation, not execution of phosphorylation. The annotation should be moved to a regulatory BP term.

Proposed replacements: regulation of I-kappaB phosphorylation

Summary: thioredoxin peroxidase activity accurately captures PRDX4 catalysis as a thioredoxin-dependent 2-Cys peroxiredoxin that reduces hydroperoxides.

Reason: This is the core molecular function of PRDX4 and is supported by both the original thioredoxin peroxidase study and structural/catalytic analysis.