Prx4 (also Jafrac2, DPx-4156; CG1274) is the Drosophila orthologue of peroxiredoxin 4, a typical 2-Cys peroxiredoxin of the AhpC/Prx1 family with an N-terminal signal peptide. It resides mainly in the lumen of the endoplasmic reticulum, where it reduces hydrogen peroxide using its peroxidatic and resolving cysteines and is regenerated by thioredoxin-type reductants, limiting ER peroxide and lipid peroxidation and protecting against oxidative stress. Under stress or strong overexpression it is redistributed to the cytosol and secreted into the hemolymph, where it can trigger JAK/STAT and Relish/NF-kB stress responses. Signal-peptide cleavage exposes an N-terminal IAP-binding motif, and in one study the cytosolic mature form bound DIAP1, displaced Dronc and promoted cell death when overexpressed.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:12356728 Jafrac2 is an IAP antagonist that promotes cell death by lib... | MODIFY | Summary: Mature Jafrac2/Prx4 binds DIAP1 through its N-terminal IAP-binding motif. Reason: Specific, motif-dependent DIAP1 binding from a single study. Binding maps to the DIAP1 BIR2 domain, so BIR domain binding is the informative replacement for bare protein binding, matching the treatment of the equivalent HtrA2 rows. The binding underlies a conditional pro-apoptotic role (competitive displacement of Dronc) shown only by gain of function, so the replacement is still regarded as non-core; GO has no term for IAP antagonism itself. Proposed replacements: BIR domain binding Supporting Evidence: PMID:12356728 We have identified the thioredoxin peroxidase Jafrac2 as an IAP-interacting protein in Drosophila cells that harbours a conserved N-terminal IAP-binding motif PMID:12356728 Collectively, these data indicate that the DIAP1 BIR2 domain is required for the binding of Jafrac2 to DIAP1 |
| GO:0005576 extracellular region | IDA PMID:11677042 The peroxiredoxin gene family in Drosophila melanogaster. | KEEP AS NON CORE | Summary: Prx4 is secreted into the hemolymph under stress or overexpression. Reason: Stimulus-dependent secretion; the steady-state location is the ER. Supporting Evidence: PMID:23271054 found a prominent increase in the dPrx levels in the hemolymph of flies subjected to septic injury, cold, or paraquat treatment |
| GO:0005576 extracellular region | IDA PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Prx4 is secreted into the hemolymph under stress or overexpression. Reason: Stimulus-dependent secretion; the steady-state location is the ER. Supporting Evidence: PMID:23271054 found a prominent increase in the dPrx levels in the hemolymph of flies subjected to septic injury, cold, or paraquat treatment |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Prx4 resides in the ER. Reason: Signal peptide and direct localization in healthy cells; conserved with PRDX4. Supporting Evidence: PMID:12356728 In healthy cells, Jafrac2 resides in the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IDA PMID:12356728 Jafrac2 is an IAP antagonist that promotes cell death by lib... | ACCEPT | Summary: Prx4 resides in the ER. Reason: Signal peptide and direct localization in healthy cells; conserved with PRDX4. Supporting Evidence: PMID:12356728 In healthy cells, Jafrac2 resides in the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IDA PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | ACCEPT | Summary: Prx4 resides in the ER. Reason: Signal peptide and direct localization in healthy cells; conserved with PRDX4. Supporting Evidence: PMID:12356728 In healthy cells, Jafrac2 resides in the endoplasmic reticulum |
| GO:0005829 cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Prx4 is released into the cytosol after apoptotic stimuli or overexpression. Reason: Stress-induced relocalization rather than the normal site of peroxidase activity. Supporting Evidence: PMID:12356728 rapidly released into the cytosol following induction of apoptosis |
| GO:0005829 cytosol | IDA PMID:12356728 Jafrac2 is an IAP antagonist that promotes cell death by lib... | KEEP AS NON CORE | Summary: Prx4 is released into the cytosol after apoptotic stimuli or overexpression. Reason: Stress-induced relocalization rather than the normal site of peroxidase activity. Supporting Evidence: PMID:12356728 rapidly released into the cytosol following induction of apoptosis |
| GO:0006979 response to oxidative stress | IBA GO_REF:0000033 | ACCEPT | Summary: Prx4 protects against oxidative stress. Reason: Knockdown increases sensitivity to oxidative stress and H2O2 flux. Supporting Evidence: PMID:23271054 resulted in greater sensitivity to oxidative stress, an elevated H₂O₂ flux, and increases in lipid peroxidation |
| GO:0006979 response to oxidative stress | IMP PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | ACCEPT | Summary: Prx4 protects against oxidative stress. Reason: Knockdown increases sensitivity to oxidative stress and H2O2 flux. Supporting Evidence: PMID:23271054 resulted in greater sensitivity to oxidative stress, an elevated H₂O₂ flux, and increases in lipid peroxidation |
| GO:0008340 determination of adult lifespan | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Electronic lifespan annotation. Reason: Knockdown of Prx4 by up to 90% had no effect on longevity; overexpression effects are mixed (low-level, under 2-fold, overexpression only tended to increase longevity, while higher overexpression was detrimental), so a lifespan-determining role is not established and the ARBA-derived term is an over-annotation. Supporting Evidence: PMID:23271054 but no effect on longevity PMID:23271054 Overexpression at low levels (<2-fold) gave reduced levels of oxidative damage and tended to show an increase in longevity |
| GO:0008379 obsolete thioredoxin peroxidase activity | IBA GO_REF:0000033 | MODIFY | Summary: Obsolete thioredoxin peroxidase activity. Reason: The obsolete term is replaced by thioredoxin-dependent peroxiredoxin activity, which Prx4 has. Proposed replacements: thioredoxin-dependent peroxiredoxin activity Supporting Evidence: PMID:11677042 The three 2-Cys Prx were also shown to be active in the thioredoxin system |
| GO:0012505 endomembrane system | HDA PMID:19317464 Mapping organelle proteins and protein complexes in Drosophi... | MODIFY | Summary: LOPIT proteomics places Prx4 in the endomembrane system. Reason: Correct but less specific; MODIFY to endoplasmic reticulum, which Prx4 already carries (IBA, IDA). Proposed replacements: endoplasmic reticulum |
| GO:0016209 antioxidant activity | IEA GO_REF:0000002 | MODIFY | Summary: General antioxidant activity. Reason: Correct parent; MODIFY to thioredoxin-dependent peroxiredoxin activity, which Prx4 already carries (IDA, IEA). Proposed replacements: thioredoxin-dependent peroxiredoxin activity |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: General oxidoreductase activity. Reason: Correct but uninformative parent; MODIFY to thioredoxin-dependent peroxiredoxin activity, which Prx4 already carries (IDA, IEA). Proposed replacements: thioredoxin-dependent peroxiredoxin activity |
| GO:0019725 cellular homeostasis | IEA GO_REF:0000117 | MODIFY | Summary: Cellular homeostasis. Reason: Correct but uninformative parent; MODIFY to cell redox homeostasis, which Prx4 already carries (IBA, IEA). Proposed replacements: cell redox homeostasis |
| GO:0042742 defense response to bacterium | IDA PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Prx4 is released after septic injury and needed for TotA induction. Reason: Stress-signalling contribution after infection rather than a direct antibacterial defense function. Supporting Evidence: PMID:23271054 dPrx4 activity is required for activation of JAK/STAT signaling in response to either septic injury or paraquat |
| GO:0042744 hydrogen peroxide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Prx4 reduces hydrogen peroxide. Reason: Recombinant protein reduces H2O2; knockdown elevates H2O2 flux. Supporting Evidence: PMID:11677042 the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol |
| GO:0042744 hydrogen peroxide catabolic process | IDA PMID:11677042 The peroxiredoxin gene family in Drosophila melanogaster. | ACCEPT | Summary: Prx4 reduces hydrogen peroxide. Reason: Recombinant protein reduces H2O2; knockdown elevates H2O2 flux. Supporting Evidence: PMID:11677042 the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol |
| GO:0042744 hydrogen peroxide catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Prx4 reduces hydrogen peroxide. Reason: Recombinant protein reduces H2O2; knockdown elevates H2O2 flux. Supporting Evidence: PMID:11677042 the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol |
| GO:0045454 cell redox homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Prx4 maintains ER redox homeostasis. Reason: Consistent with peroxide removal in the ER and increased lipid peroxidation on knockdown. Supporting Evidence: PMID:23271054 increases in lipid peroxidation |
| GO:0045454 cell redox homeostasis | IEA GO_REF:0000104 | ACCEPT | Summary: Prx4 maintains ER redox homeostasis. Reason: Consistent with peroxide removal in the ER and increased lipid peroxidation on knockdown. Supporting Evidence: PMID:23271054 increases in lipid peroxidation |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | IGI PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Secreted Prx4 elicits a JAK/STAT-mediated response. Reason: Genetic evidence places extracellular Prx4 upstream of JAK/STAT signalling, but the receptor and mechanism are unknown and the effect is largely seen with overexpression or stress-induced secretion. Supporting Evidence: PMID:23271054 dPrx4, on secretion into the hemolymph, elicits a JAK/STAT-mediated response |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | IGI PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Secreted Prx4 elicits a JAK/STAT-mediated response. Reason: Genetic evidence places extracellular Prx4 upstream of JAK/STAT signalling, but the receptor and mechanism are unknown and the effect is largely seen with overexpression or stress-induced secretion. Supporting Evidence: PMID:23271054 dPrx4, on secretion into the hemolymph, elicits a JAK/STAT-mediated response |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | IGI PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Secreted Prx4 elicits a JAK/STAT-mediated response. Reason: Genetic evidence places extracellular Prx4 upstream of JAK/STAT signalling, but the receptor and mechanism are unknown and the effect is largely seen with overexpression or stress-induced secretion. Supporting Evidence: PMID:23271054 dPrx4, on secretion into the hemolymph, elicits a JAK/STAT-mediated response |
| GO:0051920 peroxiredoxin activity | IDA PMID:33920774 Hyperoxidation of Peroxiredoxins and Effects on Physiology o... | ACCEPT | Summary: Prx4 has peroxiredoxin activity. Reason: Typical 2-Cys peroxiredoxin with demonstrated peroxide reduction. Supporting Evidence: PMID:11677042 the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol |
| GO:0051920 peroxiredoxin activity | IEA GO_REF:0000002 | ACCEPT | Summary: Prx4 has peroxiredoxin activity. Reason: Typical 2-Cys peroxiredoxin with demonstrated peroxide reduction. Supporting Evidence: PMID:11677042 the purified recombinant proteins were shown to reduce H(2)O(2) in the presence of dithiothreitol |
| GO:0070417 cellular response to cold | IDA PMID:23271054 The effect of peroxiredoxin 4 on fly physiology is a complex... | KEEP AS NON CORE | Summary: Cold exposure increases hemolymph Prx4. Reason: A secretion response to cold; not a demonstrated role in cold tolerance. Supporting Evidence: PMID:23271054 subjected to septic injury, cold, or paraquat treatment |
| GO:0097190 apoptotic signaling pathway | IGI PMID:12356728 Jafrac2 is an IAP antagonist that promotes cell death by lib... | KEEP AS NON CORE | Summary: Cytosolic Jafrac2 promotes apoptosis by displacing Dronc from DIAP1. Reason: Supported by one study using overexpression, DIAP1-binding motif mutants and dronc genetic interaction; no loss-of-function evidence shows Prx4 is required for apoptosis, so this conditional role is kept as non-core. Supporting Evidence: PMID:12356728 Jafrac2 displaces Dronc from DIAP1 by competing with Dronc for the binding of DIAP1 PMID:12356728 mutations that abolish the Jafrac2-DIAP1 interaction suppress the eye phenotype caused by Jafrac2 expression |
| GO:0097190 apoptotic signaling pathway | IMP PMID:12356728 Jafrac2 is an IAP antagonist that promotes cell death by lib... | KEEP AS NON CORE | Summary: Cytosolic Jafrac2 promotes apoptosis by displacing Dronc from DIAP1. Reason: Supported by one study using overexpression, DIAP1-binding motif mutants and dronc genetic interaction; no loss-of-function evidence shows Prx4 is required for apoptosis, so this conditional role is kept as non-core. Supporting Evidence: PMID:12356728 Jafrac2 displaces Dronc from DIAP1 by competing with Dronc for the binding of DIAP1 PMID:12356728 mutations that abolish the Jafrac2-DIAP1 interaction suppress the eye phenotype caused by Jafrac2 expression |
| GO:0098869 cellular oxidant detoxification | IEA GO_REF:0000120 | ACCEPT | Summary: Prx4 detoxifies cellular oxidants. Reason: Peroxide reduction protecting against oxidative damage. Supporting Evidence: PMID:23271054 resulted in greater sensitivity to oxidative stress |
| GO:0140824 thioredoxin-dependent peroxiredoxin activity | IDA PMID:11677042 The peroxiredoxin gene family in Drosophila melanogaster. | ACCEPT | Summary: Prx4 is a thioredoxin-dependent peroxiredoxin. Reason: 2-Cys Prx shown active in the thioredoxin system. Supporting Evidence: PMID:11677042 The three 2-Cys Prx were also shown to be active in the thioredoxin system and were, consequently, classified as thioredoxin peroxidases |
| GO:0140824 thioredoxin-dependent peroxiredoxin activity | IEA GO_REF:0000120 | ACCEPT | Summary: Prx4 is a thioredoxin-dependent peroxiredoxin. Reason: 2-Cys Prx shown active in the thioredoxin system. Supporting Evidence: PMID:11677042 The three 2-Cys Prx were also shown to be active in the thioredoxin system and were, consequently, classified as thioredoxin peroxidases |
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Download this section (compressed HTML)Q: Is Prx4/Jafrac2 required for any physiological apoptosis in vivo (loss-of-function), or is its IAP-antagonist activity restricted to overexpression and stress-released cytosolic pools?
Experiment: Generate an endogenous Prx4 allele with the mature N-terminal Ala18 of the IAP-binding motif mutated (preserving peroxidase activity) and measure Dronc/DrICE activation and cell death after UV or ER stress, compared with peroxidatic-cysteine mutants.
Hypothesis: Endogenous Prx4 released from the ER contributes to DIAP1 antagonism during stress-induced apoptosis.
Type: endogenous separation-of-function allele
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Download this section (compressed HTML)Peroxiredoxin 4 (Prx4) encodes an atypical 2-Cys peroxiredoxin that regulates hydrogen peroxide levels and participates in the formation of disulfide bonds during oxidative protein folding.
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