{"gene":"PF3D7_1368100","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2019,"finding":"PF3D7_1368100 (RPN11) contains an active MPN+ domain with the essential catalytic residues required for metalloprotease (JAMM) deubiquitinating activity, distinguishing it from the paralogous PfRpn8 and PfeIF3f which carry inactive MPN- domains lacking those residues. RPN11 was identified as one of only three proteins in the P. falciparum proteome bearing an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain.","method":"Bioinformatic domain analysis (PlasmoDB/InterPro search for IPR000555 JAB1/MPN/MOV34 metalloenzyme domain) combined with catalytic residue inspection, reported in the context of a functional chemical screen for deNeddylases in P. falciparum","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 4 / Weak — domain/residue annotation only, no direct enzymatic assay or mutagenesis performed on PfRPN11 itself in this study","pmids":["31658303"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PF3D7_1368100 (RPN11) protein levels are translationally upregulated in ART-resistant P. falciparum (Dd2R539T) after dihydroartemisinin (DHA) pulse, with its transcript level simultaneously decreased, indicating post-transcriptional/translational control. The gene displays LysAAA and AspGAT codon bias and is classified as essential.","method":"Integrated proteomic (mass spectrometry) and transcriptomic analysis of synchronized ART-sensitive vs. ART-resistant (Dd2R539T) parasites before and after DHA pulse, with codon usage analysis","journal":"Nature microbiology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — observational proteomic/transcriptomic correlation; no direct functional assay performed on RPN11 itself","pmids":["38632343"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2R539T"}]}],"current_model":"PF3D7_1368100 (RPN11) is a putative 19S proteasome lid subunit in P. falciparum that harbors an active MPN+ (JAMM) metalloprotease domain predicted to confer deubiquitinating activity at the proteasome, with its protein levels subject to translational upregulation in artemisinin-resistant parasites; no direct enzymatic or structural experiments on PfRPN11 itself have been reported in the available literature."},"narrative":{"mechanistic_narrative":"PF3D7_1368100 (RPN11) is a putative 19S proteasome lid subunit in Plasmodium falciparum whose characterization in the available corpus rests on two indirect lines of evidence. Bioinformatic analysis places RPN11 among only three P. falciparum proteins carrying an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain, and unlike its paralogs PfRpn8 and PfeIF3f — which bear catalytically inactive MPN- domains — RPN11 retains the essential catalytic residues of an active MPN+ (JAMM) metalloprotease domain predicted to confer deubiquitinating activity [PMID:31658303]. In artemisinin-resistant parasites (Dd2R539T), RPN11 protein levels are translationally upregulated after a dihydroartemisinin pulse while its transcript level falls, indicating post-transcriptional control, and the gene is classified as essential [PMID:38632343]. Beyond these domain-level and observational findings, no direct enzymatic, mutagenic, or structural experiments on PfRPN11 itself have been reported in the available corpus.","teleology":[{"year":2019,"claim":"To ask whether P. falciparum encodes a proteasomal deubiquitinase, domain analysis established that RPN11 uniquely retains an active MPN+ (JAMM) metalloprotease domain, distinguishing it from catalytically dead paralogs.","evidence":"Bioinformatic IPR000555 domain search and catalytic-residue inspection in the context of a deNeddylase chemical screen","pmids":["31658303"],"confidence":"Low","gaps":["No direct enzymatic assay or mutagenesis performed on PfRPN11 to confirm deubiquitinating activity","No structural model of the domain in the assembled proteasome","Predicted substrate specificity not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"To probe how the proteasome contributes to artemisinin resistance, proteomic/transcriptomic profiling showed RPN11 protein is translationally upregulated after DHA pulse in resistant parasites while its transcript falls, pointing to post-transcriptional regulation and essentiality.","evidence":"Integrated mass spectrometry and transcriptomics of synchronized ART-sensitive vs. resistant Dd2R539T parasites before/after DHA pulse, with codon-usage analysis","pmids":["38632343"],"confidence":"Low","gaps":["Observational correlation only; no functional assay linking RPN11 levels to resistance","Mechanism of translational upregulation not defined","Essentiality claim not supported by a direct genetic knockout in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2R539T"}]},{"year":null,"claim":"Whether PfRPN11 actually possesses deubiquitinating activity, how it assembles into and functions within the 19S proteasome, and whether its regulation causally contributes to artemisinin resistance remain undetermined.","evidence":"No direct biochemical, structural, or genetic experiments on PfRPN11 itself in the available corpus","pmids":[],"confidence":"Low","gaps":["No reconstitution or in vitro assay of PfRPN11 metalloprotease/DUB activity","No structure or proteasome-assembly data for PfRPN11","No causal link between RPN11 upregulation and ART resistance"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["19S proteasome regulatory particle (lid) subunit, putative"],"partners":[],"other_free_text":["One of only three P. falciparum proteins bearing an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain; carries an active MPN+ domain distinct from the inactive MPN- domains of paralogs PfRpn8 and PfeIF3f [#0]","Protein translationally upregulated with transcript decreased after DHA pulse in ART-resistant Dd2R539T parasites; classified as essential [#1]","No direct enzymatic, mutagenic, or structural experiments on PfRPN11 itself reported in the available corpus"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24533266","id":"PMC_24533266","title":"The proteasome of malaria parasites: A multi-stage drug target for chemotherapeutic intervention?","date":"2012","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/24533266","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40278767","id":"","title":"Combating Malaria: Targeting the Ubiquitin-Proteasome System to Conquer Drug Resistance.","date":"2025","source":"Tropical medicine and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/40278767","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RPN11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31658303","id":"","title":"Nedd8 hydrolysis by UCH proteases in Plasmodium parasites.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31658303","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RPN11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38632343","id":"","title":"tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum.","date":"2024","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38632343","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RPN11"],"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":["RPN11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7398,"output_tokens":777,"usd":0.016924,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5420,"output_tokens":1829,"usd":0.036413,"stage2_stop_reason":"end_turn"},"total_usd":0.053337,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PF3D7_1368100 (RPN11) contains an active MPN+ domain with the essential catalytic residues required for metalloprotease (JAMM) deubiquitinating activity, distinguishing it from the paralogous PfRpn8 and PfeIF3f which carry inactive MPN- domains lacking those residues. RPN11 was identified as one of only three proteins in the P. falciparum proteome bearing an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain.\",\n      \"method\": \"Bioinformatic domain analysis (PlasmoDB/InterPro search for IPR000555 JAB1/MPN/MOV34 metalloenzyme domain) combined with catalytic residue inspection, reported in the context of a functional chemical screen for deNeddylases in P. falciparum\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — domain/residue annotation only, no direct enzymatic assay or mutagenesis performed on PfRPN11 itself in this study\",\n      \"pmids\": [\"31658303\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PF3D7_1368100 (RPN11) protein levels are translationally upregulated in ART-resistant P. falciparum (Dd2R539T) after dihydroartemisinin (DHA) pulse, with its transcript level simultaneously decreased, indicating post-transcriptional/translational control. The gene displays LysAAA and AspGAT codon bias and is classified as essential.\",\n      \"method\": \"Integrated proteomic (mass spectrometry) and transcriptomic analysis of synchronized ART-sensitive vs. ART-resistant (Dd2R539T) parasites before and after DHA pulse, with codon usage analysis\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — observational proteomic/transcriptomic correlation; no direct functional assay performed on RPN11 itself\",\n      \"pmids\": [\"38632343\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2R539T\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1368100 (RPN11) is a putative 19S proteasome lid subunit in P. falciparum that harbors an active MPN+ (JAMM) metalloprotease domain predicted to confer deubiquitinating activity at the proteasome, with its protein levels subject to translational upregulation in artemisinin-resistant parasites; no direct enzymatic or structural experiments on PfRPN11 itself have been reported in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1368100 (RPN11) is a putative 19S proteasome lid subunit in Plasmodium falciparum whose characterization in the available corpus rests on two indirect lines of evidence. Bioinformatic analysis places RPN11 among only three P. falciparum proteins carrying an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain, and unlike its paralogs PfRpn8 and PfeIF3f — which bear catalytically inactive MPN- domains — RPN11 retains the essential catalytic residues of an active MPN+ (JAMM) metalloprotease domain predicted to confer deubiquitinating activity [#0]. In artemisinin-resistant parasites (Dd2R539T), RPN11 protein levels are translationally upregulated after a dihydroartemisinin pulse while its transcript level falls, indicating post-transcriptional control, and the gene is classified as essential [#1]. Beyond these domain-level and observational findings, no direct enzymatic, mutagenic, or structural experiments on PfRPN11 itself have been reported in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"To ask whether P. falciparum encodes a proteasomal deubiquitinase, domain analysis established that RPN11 uniquely retains an active MPN+ (JAMM) metalloprotease domain, distinguishing it from catalytically dead paralogs.\",\n      \"evidence\": \"Bioinformatic IPR000555 domain search and catalytic-residue inspection in the context of a deNeddylase chemical screen\",\n      \"pmids\": [\n        \"31658303\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct enzymatic assay or mutagenesis performed on PfRPN11 to confirm deubiquitinating activity\",\n        \"No structural model of the domain in the assembled proteasome\",\n        \"Predicted substrate specificity not tested\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To probe how the proteasome contributes to artemisinin resistance, proteomic/transcriptomic profiling showed RPN11 protein is translationally upregulated after DHA pulse in resistant parasites while its transcript falls, pointing to post-transcriptional regulation and essentiality.\",\n      \"evidence\": \"Integrated mass spectrometry and transcriptomics of synchronized ART-sensitive vs. resistant Dd2R539T parasites before/after DHA pulse, with codon-usage analysis\",\n      \"pmids\": [\n        \"38632343\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Observational correlation only; no functional assay linking RPN11 levels to resistance\",\n        \"Mechanism of translational upregulation not defined\",\n        \"Essentiality claim not supported by a direct genetic knockout in this study\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"Dd2R539T\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PfRPN11 actually possesses deubiquitinating activity, how it assembles into and functions within the 19S proteasome, and whether its regulation causally contributes to artemisinin resistance remain undetermined.\",\n      \"evidence\": \"No direct biochemical, structural, or genetic experiments on PfRPN11 itself in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstitution or in vitro assay of PfRPN11 metalloprotease/DUB activity\",\n        \"No structure or proteasome-assembly data for PfRPN11\",\n        \"No causal link between RPN11 upregulation and ART resistance\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0008237\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0101005\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0043161\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"19S proteasome regulatory particle (lid) subunit, putative\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"One of only three P. falciparum proteins bearing an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain; carries an active MPN+ domain distinct from the inactive MPN- domains of paralogs PfRpn8 and PfeIF3f [#0]\",\n      \"Protein translationally upregulated with transcript decreased after DHA pulse in ART-resistant Dd2R539T parasites; classified as essential [#1]\",\n      \"No direct enzymatic, mutagenic, or structural experiments on PfRPN11 itself reported in the available corpus\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1368100","name":null,"product":"26S proteasome regulatory subunit RPN11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1144000","name":null,"product":"26S proteasome regulatory subunit RPN11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1103100","name":null,"product":"26S proteasome regulatory subunit RPN11, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RPN11","evaluation":null}