{"gene":"PF3D7_0507700","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2008,"finding":"NPL4 (PF3D7_0507700; annotated as PFE0380c) was predicted by BLASTP to be a component of the Cdc48-NPL4-Ufd1 escort pathway in P. falciparum, suggesting membership in a conserved AAA-ATPase complex involved in ubiquitin-dependent ERAD and proteasomal degradation; clear orthologs were also identified in P. yoelii, C. parvum, C. hominis, and T. gondii.","method":"Bioinformatic prediction (BLASTP homology search and OrthoMCL-DB ortholog retrieval)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of NPL4 function performed in this study","pmids":["18545708"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"NPL4 (PF3D7_0507700) is proposed to be part of the CDC48-UFD1-NPL4 AAA-ATPase complex that extracts poly-ubiquitylated misfolded proteins from the ER membrane and shuttles them to the 26S proteasome during ERAD; this placement is based on analogy to yeast/human systems and the characterization of the flanking ERAD components (PfUBA1, PfUBC, PfHRD1) rather than direct experimental interrogation of NPL4 itself.","method":"Contextual inference from ERAD pathway characterization (in vitro ubiquitylation assay and immunofluorescence of other ERAD components; NPL4 itself not directly assayed)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — NPL4 is placed in a model by analogy; no direct experiment on NPL4 was performed in this paper","pmids":["22912882"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"NPL4 (PF3D7_0507700) is predicted by bioinformatics and pathway analogy to function as a subunit of the conserved Cdc48-NPL4-Ufd1 AAA-ATPase complex in P. falciparum, where it would participate in extracting poly-ubiquitylated substrates from the ER membrane for proteasomal degradation via the ERAD pathway; no direct experimental characterization of NPL4 itself has been reported in the available literature."},"narrative":{"mechanistic_narrative":"NPL4 (PF3D7_0507700; annotated PFE0380c) has been identified in the available corpus only by computational prediction, which places it as a component of the conserved Cdc48-NPL4-Ufd1 AAA-ATPase escort complex in P. falciparum, a complex implicated in ubiquitin-dependent extraction of misfolded proteins from the ER membrane for proteasomal degradation (ERAD) [PMID:18545708]. Its membership in this complex and its participation in ERAD are inferred by analogy to yeast and human systems and from characterization of flanking ERAD components rather than from any direct assay of NPL4 itself [PMID:22912882]. Beyond these predictions, no experimental characterization of NPL4's function, interactions, localization, or substrates has been reported in the available corpus.","teleology":[{"year":2008,"claim":"To place an uncharacterized parasite gene into a functional pathway, homology searching asked whether PF3D7_0507700 belongs to a conserved degradation machinery, establishing its predicted identity as a Cdc48-NPL4-Ufd1 escort complex subunit conserved across apicomplexans.","evidence":"BLASTP homology search and OrthoMCL-DB ortholog retrieval identifying orthologs in P. yoelii, C. parvum, C. hominis, and T. gondii","pmids":["18545708"],"confidence":"Low","gaps":["Computational prediction only; no experimental validation of NPL4 function or complex membership was performed","No demonstration that the parasite protein physically associates with Cdc48/Ufd1","Localization of NPL4 not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"To situate NPL4 within a specific cellular process, ERAD pathway characterization in P. falciparum modeled it as part of the CDC48-UFD1-NPL4 complex extracting poly-ubiquitylated substrates from the ER for the 26S proteasome, but this placement rested on analogy and on the other ERAD components rather than on NPL4 itself.","evidence":"In vitro ubiquitylation assay and immunofluorescence of other ERAD components (PfUBA1, PfUBC, PfHRD1); NPL4 not directly assayed","pmids":["22912882"],"confidence":"Low","gaps":["NPL4 itself was not experimentally interrogated in this study","No direct evidence of NPL4 participation in substrate extraction or proteasomal shuttling","Interaction of NPL4 with Cdc48 and Ufd1 in the parasite unconfirmed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Direct experimental characterization of NPL4 — its physical partners, localization, and functional role in ERAD in P. falciparum — remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical demonstration of Cdc48-NPL4-Ufd1 complex assembly in the parasite","No genetic or knockdown evidence for NPL4 function in ERAD","No experimentally determined subcellular localization for NPL4"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Cdc48-NPL4-Ufd1 AAA-ATPase complex (predicted)"],"partners":["CDC48/CDC48 (PREDICTED)","UFD1/UFD1 (PREDICTED)"],"other_free_text":["Membership of PF3D7_0507700 in the Cdc48-NPL4-Ufd1 complex and its role in ERAD are supported only by bioinformatic prediction and pathway analogy; NPL4 itself has not been directly experimentally characterized in the available corpus.","Orthologs predicted in P. yoelii, C. parvum, C. hominis, and T. gondii [#0]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19502583","id":"PMC_19502583","title":"An unusual ERAD-like complex is targeted to the apicoplast of Plasmodium falciparum.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/19502583","citation_count":109,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27911910","id":"","title":"Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27911910","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["NPL4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22912882","id":"","title":"Characterization of the ubiquitylating components of the human malaria parasite's protein degradation pathway.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22912882","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["NPL4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18545708","id":"","title":"Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18545708","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["NPL4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6549,"output_tokens":750,"usd":0.015449,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5351,"output_tokens":1621,"usd":0.03364,"stage2_stop_reason":"end_turn"},"total_usd":0.049089,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"NPL4 (PF3D7_0507700; annotated as PFE0380c) was predicted by BLASTP to be a component of the Cdc48-NPL4-Ufd1 escort pathway in P. falciparum, suggesting membership in a conserved AAA-ATPase complex involved in ubiquitin-dependent ERAD and proteasomal degradation; clear orthologs were also identified in P. yoelii, C. parvum, C. hominis, and T. gondii.\",\n      \"method\": \"Bioinformatic prediction (BLASTP homology search and OrthoMCL-DB ortholog retrieval)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of NPL4 function performed in this study\",\n      \"pmids\": [\"18545708\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NPL4 (PF3D7_0507700) is proposed to be part of the CDC48-UFD1-NPL4 AAA-ATPase complex that extracts poly-ubiquitylated misfolded proteins from the ER membrane and shuttles them to the 26S proteasome during ERAD; this placement is based on analogy to yeast/human systems and the characterization of the flanking ERAD components (PfUBA1, PfUBC, PfHRD1) rather than direct experimental interrogation of NPL4 itself.\",\n      \"method\": \"Contextual inference from ERAD pathway characterization (in vitro ubiquitylation assay and immunofluorescence of other ERAD components; NPL4 itself not directly assayed)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — NPL4 is placed in a model by analogy; no direct experiment on NPL4 was performed in this paper\",\n      \"pmids\": [\"22912882\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"NPL4 (PF3D7_0507700) is predicted by bioinformatics and pathway analogy to function as a subunit of the conserved Cdc48-NPL4-Ufd1 AAA-ATPase complex in P. falciparum, where it would participate in extracting poly-ubiquitylated substrates from the ER membrane for proteasomal degradation via the ERAD pathway; no direct experimental characterization of NPL4 itself has been reported in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPL4 (PF3D7_0507700; annotated PFE0380c) has been identified in the available corpus only by computational prediction, which places it as a component of the conserved Cdc48-NPL4-Ufd1 AAA-ATPase escort complex in P. falciparum, a complex implicated in ubiquitin-dependent extraction of misfolded proteins from the ER membrane for proteasomal degradation (ERAD) [#0]. Its membership in this complex and its participation in ERAD are inferred by analogy to yeast and human systems and from characterization of flanking ERAD components rather than from any direct assay of NPL4 itself [#1]. Beyond these predictions, no experimental characterization of NPL4's function, interactions, localization, or substrates has been reported in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"To place an uncharacterized parasite gene into a functional pathway, homology searching asked whether PF3D7_0507700 belongs to a conserved degradation machinery, establishing its predicted identity as a Cdc48-NPL4-Ufd1 escort complex subunit conserved across apicomplexans.\",\n      \"evidence\": \"BLASTP homology search and OrthoMCL-DB ortholog retrieval identifying orthologs in P. yoelii, C. parvum, C. hominis, and T. gondii\",\n      \"pmids\": [\"18545708\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only; no experimental validation of NPL4 function or complex membership was performed\",\n        \"No demonstration that the parasite protein physically associates with Cdc48/Ufd1\",\n        \"Localization of NPL4 not determined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"To situate NPL4 within a specific cellular process, ERAD pathway characterization in P. falciparum modeled it as part of the CDC48-UFD1-NPL4 complex extracting poly-ubiquitylated substrates from the ER for the 26S proteasome, but this placement rested on analogy and on the other ERAD components rather than on NPL4 itself.\",\n      \"evidence\": \"In vitro ubiquitylation assay and immunofluorescence of other ERAD components (PfUBA1, PfUBC, PfHRD1); NPL4 not directly assayed\",\n      \"pmids\": [\"22912882\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"NPL4 itself was not experimentally interrogated in this study\",\n        \"No direct evidence of NPL4 participation in substrate extraction or proteasomal shuttling\",\n        \"Interaction of NPL4 with Cdc48 and Ufd1 in the parasite unconfirmed\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Direct experimental characterization of NPL4 — its physical partners, localization, and functional role in ERAD in P. falciparum — remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical demonstration of Cdc48-NPL4-Ufd1 complex assembly in the parasite\",\n        \"No genetic or knockdown evidence for NPL4 function in ERAD\",\n        \"No experimentally determined subcellular localization for NPL4\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0030433\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"Cdc48-NPL4-Ufd1 AAA-ATPase complex (predicted)\"],\n    \"partners\": [\"Cdc48/CDC48 (predicted)\", \"Ufd1/UFD1 (predicted)\"],\n    \"other_free_text\": [\n      \"Membership of PF3D7_0507700 in the Cdc48-NPL4-Ufd1 complex and its role in ERAD are supported only by bioinformatic prediction and pathway analogy; NPL4 itself has not been directly experimentally characterized in the available corpus.\",\n      \"Orthologs predicted in P. yoelii, C. parvum, C. hominis, and T. gondii [#0].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0507700","name":null,"product":"nuclear protein localization protein 4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1107300","name":null,"product":"nuclear protein localization protein 4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1025900","name":null,"product":"nuclear protein localization protein 4, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"NPL4","evaluation":null}