{"gene":"PF3D7_1449700","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2018,"finding":"Recombinant PfRrp6 (PF3D7_1449700) exhibited catalytic (ribonuclease) activity toward single-stranded RNA (ssRNA) in vitro, establishing it as a catalytically active component of the P. falciparum RNA exosome-like complex. Its subcellular localization was determined to be cytoplasmic by indirect immunofluorescence.","method":"In vitro RNA degradation assay with recombinant protein; indirect immunofluorescence for localization; Western blot for protein expression confirmation","journal":"The Journal of eukaryotic microbiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic activity demonstrated with recombinant protein, but single lab, single study, no mutagenesis or structural validation","pmids":["29664138"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Knockdown of PfRrp6 (PF3D7_1449700) in P. falciparum stabilized nascent RUF6 ncRNA transcripts, causing their accumulation. Accumulated RUF6 ncRNAs triggered local chromatin remodeling at adjacent var gene loci, activating those genes. ChIRP-seq further showed that excess RUF6 ncRNA interacted directly with distal heterochromatic regions, causing global derepression of heterochromatic genes (including all variant gene families and the sexual commitment regulator ap2-g). Thus RRP6 controls heterochromatic gene silencing through RUF6 ncRNA decay.","method":"Genetic knockdown (loss-of-function), genome-wide multiomics (ChIRP-seq), chromatin analysis, transcriptomics","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific phenotypic readouts combined with multiple orthogonal genome-wide methods (ChIRP-seq, chromatin profiling, transcriptomics) in a single rigorous study","pmids":["32487761"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1449700 (RRP6) is a catalytically active ssRNA exonuclease of the P. falciparum RNA exosome-like complex that localizes to the cytoplasm and, in the nucleus, degrades RUF6 ncRNA nascent transcripts to maintain their singular expression; when RRP6 is lost, RUF6 ncRNAs accumulate, remodel local chromatin at adjacent var gene loci, and interact with distal heterochromatic regions to globally derepress heterochromatic genes including virulence gene families and the sexual commitment factor ap2-g."},"narrative":{"mechanistic_narrative":"PF3D7_1449700 (RRP6) is a catalytically active ribonuclease of the Plasmodium falciparum RNA exosome-like complex that couples ncRNA turnover to heterochromatic gene silencing [PMID:29664138, PMID:32487761]. Recombinant RRP6 degrades single-stranded RNA in vitro, establishing it as an enzymatically active exonuclease, and localizes to the cytoplasm by immunofluorescence [PMID:29664138]. In the control of variant gene expression, RRP6 mediates decay of nascent RUF6 ncRNA transcripts: knockdown stabilizes and accumulates RUF6 ncRNA, which remodels local chromatin at adjacent var loci and interacts with distal heterochromatic regions, globally derepressing heterochromatic gene families and the sexual commitment regulator ap2-g [PMID:32487761]. Beyond its ssRNA exonuclease activity and this RUF6-dependent silencing role, no further mechanistic detail (e.g. catalytic-residue mapping, structural model, or defined complex composition) has been characterized for RRP6 in the available corpus.","teleology":[{"year":2018,"claim":"Whether PF3D7_1449700 is an active nuclease or merely a structural subunit of the exosome-like complex was unresolved; demonstrating intrinsic catalytic activity established it as an enzymatically functional component.","evidence":"In vitro RNA degradation assay with recombinant PfRrp6 protein plus indirect immunofluorescence for localization","pmids":["29664138"],"confidence":"Medium","gaps":["No catalytic-residue mutagenesis or structural validation of the active site","Single lab, single study","Cytoplasmic localization does not by itself explain a nuclear silencing role"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The biological substrate and function of RRP6 nuclease activity in vivo were unknown; loss-of-function showed it degrades RUF6 ncRNA to enforce heterochromatic gene silencing, linking RNA decay to epigenetic control of virulence and sexual commitment genes.","evidence":"Genetic knockdown in P. falciparum with ChIRP-seq, chromatin profiling, and transcriptomics","pmids":["32487761"],"confidence":"High","gaps":["Does not establish whether RRP6 acts directly on RUF6 in the nucleus or via the full exosome complex","Composition of the P. falciparum exosome-like complex containing RRP6 not defined here","Reconciliation of cytoplasmic localization [#0] with a nuclear ncRNA-decay function not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether RRP6's ssRNA exonuclease activity is directly responsible for RUF6 ncRNA turnover in vivo, and the identity of its exosome partner subunits, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic-dead rescue linking enzymatic activity to the silencing phenotype","No defined subunit composition of the RRP6-containing exosome-like complex","No structural model"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["RNA exosome-like complex (P. falciparum)"],"partners":["RUF6 NCRNA (SUBSTRATE)"],"other_free_text":["RRP6 knockdown derepresses variant/virulence gene families and the sexual commitment regulator ap2-g via RUF6 ncRNA accumulation [#1].","Excess RUF6 ncRNA interacts with distal heterochromatic regions (ChIRP-seq) and remodels local chromatin at adjacent var loci [#1]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32487761","id":"PMC_32487761","title":"Rrp6 Regulates Heterochromatic Gene Silencing via ncRNA RUF6 Decay in Malaria Parasites.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32487761","citation_count":26,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["RRP6","PfRRP6"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29664138","id":"PMC_29664138","title":"Characterization of the Catalytic Subunits of the RNA Exosome-like Complex in Plasmodium falciparum.","date":"2018","source":"The Journal of eukaryotic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29664138","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfRRP6"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4087,"output_tokens":800,"usd":0.012131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5470,"output_tokens":1761,"usd":0.035687,"stage2_stop_reason":"end_turn"},"total_usd":0.047818,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Recombinant PfRrp6 (PF3D7_1449700) exhibited catalytic (ribonuclease) activity toward single-stranded RNA (ssRNA) in vitro, establishing it as a catalytically active component of the P. falciparum RNA exosome-like complex. Its subcellular localization was determined to be cytoplasmic by indirect immunofluorescence.\",\n      \"method\": \"In vitro RNA degradation assay with recombinant protein; indirect immunofluorescence for localization; Western blot for protein expression confirmation\",\n      \"journal\": \"The Journal of eukaryotic microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic activity demonstrated with recombinant protein, but single lab, single study, no mutagenesis or structural validation\",\n      \"pmids\": [\"29664138\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of PfRrp6 (PF3D7_1449700) in P. falciparum stabilized nascent RUF6 ncRNA transcripts, causing their accumulation. Accumulated RUF6 ncRNAs triggered local chromatin remodeling at adjacent var gene loci, activating those genes. ChIRP-seq further showed that excess RUF6 ncRNA interacted directly with distal heterochromatic regions, causing global derepression of heterochromatic genes (including all variant gene families and the sexual commitment regulator ap2-g). Thus RRP6 controls heterochromatic gene silencing through RUF6 ncRNA decay.\",\n      \"method\": \"Genetic knockdown (loss-of-function), genome-wide multiomics (ChIRP-seq), chromatin analysis, transcriptomics\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific phenotypic readouts combined with multiple orthogonal genome-wide methods (ChIRP-seq, chromatin profiling, transcriptomics) in a single rigorous study\",\n      \"pmids\": [\"32487761\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1449700 (RRP6) is a catalytically active ssRNA exonuclease of the P. falciparum RNA exosome-like complex that localizes to the cytoplasm and, in the nucleus, degrades RUF6 ncRNA nascent transcripts to maintain their singular expression; when RRP6 is lost, RUF6 ncRNAs accumulate, remodel local chromatin at adjacent var gene loci, and interact with distal heterochromatic regions to globally derepress heterochromatic genes including virulence gene families and the sexual commitment factor ap2-g.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1449700 (RRP6) is a catalytically active ribonuclease of the Plasmodium falciparum RNA exosome-like complex that couples ncRNA turnover to heterochromatic gene silencing [#0, #1]. Recombinant RRP6 degrades single-stranded RNA in vitro, establishing it as an enzymatically active exonuclease, and localizes to the cytoplasm by immunofluorescence [#0]. In the control of variant gene expression, RRP6 mediates decay of nascent RUF6 ncRNA transcripts: knockdown stabilizes and accumulates RUF6 ncRNA, which remodels local chromatin at adjacent var loci and interacts with distal heterochromatic regions, globally derepressing heterochromatic gene families and the sexual commitment regulator ap2-g [#1]. Beyond its ssRNA exonuclease activity and this RUF6-dependent silencing role, no further mechanistic detail (e.g. catalytic-residue mapping, structural model, or defined complex composition) has been characterized for RRP6 in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether PF3D7_1449700 is an active nuclease or merely a structural subunit of the exosome-like complex was unresolved; demonstrating intrinsic catalytic activity established it as an enzymatically functional component.\",\n      \"evidence\": \"In vitro RNA degradation assay with recombinant PfRrp6 protein plus indirect immunofluorescence for localization\",\n      \"pmids\": [\"29664138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No catalytic-residue mutagenesis or structural validation of the active site\",\n        \"Single lab, single study\",\n        \"Cytoplasmic localization does not by itself explain a nuclear silencing role\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The biological substrate and function of RRP6 nuclease activity in vivo were unknown; loss-of-function showed it degrades RUF6 ncRNA to enforce heterochromatic gene silencing, linking RNA decay to epigenetic control of virulence and sexual commitment genes.\",\n      \"evidence\": \"Genetic knockdown in P. falciparum with ChIRP-seq, chromatin profiling, and transcriptomics\",\n      \"pmids\": [\"32487761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not establish whether RRP6 acts directly on RUF6 in the nucleus or via the full exosome complex\",\n        \"Composition of the P. falciparum exosome-like complex containing RRP6 not defined here\",\n        \"Reconciliation of cytoplasmic localization [#0] with a nuclear ncRNA-decay function not resolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether RRP6's ssRNA exonuclease activity is directly responsible for RUF6 ncRNA turnover in vivo, and the identity of its exosome partner subunits, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No catalytic-dead rescue linking enzymatic activity to the silencing phenotype\",\n        \"No defined subunit composition of the RRP6-containing exosome-like complex\",\n        \"No structural model\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004532\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000175\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003727\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071028\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031507\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0045814\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"RNA exosome-like complex (P. falciparum)\"\n    ],\n    \"partners\": [\n      \"RUF6 ncRNA (substrate)\"\n    ],\n    \"other_free_text\": [\n      \"RRP6 knockdown derepresses variant/virulence gene families and the sexual commitment regulator ap2-g via RUF6 ncRNA accumulation [#1].\",\n      \"Excess RUF6 ncRNA interacts with distal heterochromatic regions (ChIRP-seq) and remodels local chromatin at adjacent var loci [#1].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1449700","name":null,"product":"exosome complex exonuclease RRP6","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1313400","name":null,"product":"exosome complex exonuclease RRP6, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1232400","name":null,"product":"exosome complex exonuclease RRP6, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"RRP6","evaluation":null}