{"gene":"TG_223680","gene_symbol":"DSK2","run_date":"2026-09-08T11:06:41","timeline":{"discoveries":[{"year":2020,"finding":"T. gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein that localizes to the cytoplasm and nucleus, and its deletion (along with DDI1 and RAD23) leads to accumulation of ubiquitinylated proteins, demonstrating its role in escorting ubiquitinylated substrates to the proteasome for degradation.","method":"Gene knockout (triple-KO of DDI1, RAD23, DSK2), subcellular localization (cytoplasm/nucleus), and ubiquitinated protein accumulation assay","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined molecular phenotype (ubiquitinylated protein accumulation) and localization data, but effects are from triple-KO so DSK2-specific contribution is not isolated","pmids":["32808330"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]},{"year":2020,"finding":"Deletion of UBL-UBA shuttle proteins including DSK2 results in asynchronous cell division of T. gondii parasites, establishing a role for these proteins in coordinating synchronous cell division.","method":"Triple-gene knockout (DDI1, RAD23, DSK2) with cell division phenotype analysis","journal":"FASEB Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell division phenotype observed in triple-KO only, DSK2-specific contribution cannot be attributed individually","pmids":["32808330"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]},{"year":2021,"finding":"Deletion of UBL-UBA shuttle proteins including DSK2 causes selective accumulation of ubiquitinated proteins in the nucleus and aberrant DNA replication, and leads to mistargeting and accumulation of the virulence effector ROP18, which results in aberrant recruitment of host immunity-related GTPase Irgb6 to the parasitophorous vacuole membrane.","method":"Shuttle protein mutant strain analysis, subcellular fractionation/localization of ubiquitinated proteins, ROP18 localization, and host Irgb6 recruitment assay","journal":"FASEB Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic findings from triple-KO; DSK2-specific role cannot be separated from DDI1/RAD23 contributions","pmids":["34727385"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]}],"current_model":"T. gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein that localizes to the cytoplasm and nucleus and functions as part of the ubiquitin-proteasome system to escort ubiquitinylated proteins to the proteasome for degradation, with loss of DSK2 (together with DDI1 and RAD23) causing accumulation of ubiquitinated proteins (particularly in the nucleus), aberrant DNA replication, asynchronous cell division, and mistargeting of the virulence effector ROP18."},"narrative":{"mechanistic_narrative":"Toxoplasma gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein of the ubiquitin-proteasome system that localizes to the cytoplasm and nucleus and functions to escort ubiquitinylated substrates to the proteasome for degradation [PMID:32808330]. It acts redundantly with the shuttle proteins DDI1 and RAD23: combined loss of the three proteins causes accumulation of ubiquitinylated proteins [PMID:32808330]. Because all reported mechanistic phenotypes derive from a triple knockout, the individual contribution of DSK2 has not been isolated in the available corpus.","teleology":[{"year":2020,"claim":"Establishing whether T. gondii encodes functional ubiquitin-shuttle machinery, this work identified DSK2 as a cytoplasmic/nuclear UBL-UBA shuttle protein whose loss (with DDI1 and RAD23) triggers accumulation of ubiquitinylated proteins, placing it in the proteasomal degradation route.","evidence":"Triple-gene knockout (DDI1, RAD23, DSK2), subcellular localization, and ubiquitinated-protein accumulation assay in TGGT1","pmids":["32808330"],"confidence":"Medium","gaps":["DSK2-specific contribution cannot be separated from DDI1/RAD23 in a triple-KO","no direct substrate of DSK2 identified","no reconstitution of DSK2-proteasome escort in vitro"],"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]},{"year":2020,"claim":"Testing whether shuttle-protein function extends beyond proteostasis, deletion of the shuttle proteins including DSK2 produced asynchronous cell division, linking the ubiquitin-shuttle machinery to coordination of synchronous parasite replication.","evidence":"Triple-gene knockout (DDI1, RAD23, DSK2) with cell division phenotype analysis in TGGT1","pmids":["32808330"],"confidence":"Low","gaps":["phenotype observed only in triple-KO; DSK2-specific role not attributed","mechanism linking shuttle function to division timing unknown"],"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]},{"year":2021,"claim":"Probing the downstream consequences of shuttle-protein loss, mutation of the shuttle proteins including DSK2 caused nuclear accumulation of ubiquitinated proteins, aberrant DNA replication, and mistargeting of the virulence effector ROP18, which in turn led to aberrant host Irgb6 recruitment to the parasitophorous vacuole membrane.","evidence":"Shuttle-protein mutant analysis, subcellular localization of ubiquitinated proteins, ROP18 localization, and host Irgb6 recruitment assay in TGGT1","pmids":["34727385"],"confidence":"Low","gaps":["findings derive from triple-KO; DSK2-specific role not separable from DDI1/RAD23","mechanistic link between shuttle-protein loss and ROP18 mistargeting not defined","whether DSK2 directly handles ROP18 as a substrate is untested"],"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]},{"year":null,"claim":"The specific, non-redundant contribution of DSK2 — its direct substrates and how its loss individually affects proteostasis, cell division, and virulence-effector targeting — remains unresolved because all phenotypes to date derive from combined deletion with DDI1 and RAD23.","evidence":"No single-gene DSK2 characterization in the available corpus","pmids":[],"confidence":"Low","gaps":["no single DSK2 knockout phenotype reported","no DSK2-specific substrate identified","no structural or biochemical characterization of DSK2 UBL/UBA domains"],"attribution":[{"species":"Toxoplasma gondii","strain":"TGGT1"}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["DDI1","RAD23"],"other_free_text":["Loss of the DSK2/DDI1/RAD23 shuttle proteins causes mistargeting of the virulence effector ROP18 and aberrant host Irgb6 recruitment to the parasitophorous vacuole membrane [#2].","All reported DSK2 phenotypes derive from triple knockout with DDI1 and RAD23; DSK2-specific contribution has not been isolated."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"32808330","id":"PMC_32808330","title":"Toxoplasma gondii UBL-UBA shuttle proteins contribute to the degradation of ubiquitinylated proteins and are important for synchronous cell division and virulence.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32808330","citation_count":24,"is_preprint":false},{"pmid":"34727385","id":"PMC_34727385","title":"Toxoplasma gondii UBL-UBA shuttle proteins regulate several important cellular processes.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34727385","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3323,"output_tokens":943,"usd":0.012057,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5797,"output_tokens":2215,"usd":0.04218,"stage2_stop_reason":"end_turn"},"total_usd":0.054237,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"T. gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein that localizes to the cytoplasm and nucleus, and its deletion (along with DDI1 and RAD23) leads to accumulation of ubiquitinylated proteins, demonstrating its role in escorting ubiquitinylated substrates to the proteasome for degradation.\",\n      \"method\": \"Gene knockout (triple-KO of DDI1, RAD23, DSK2), subcellular localization (cytoplasm/nucleus), and ubiquitinated protein accumulation assay\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined molecular phenotype (ubiquitinylated protein accumulation) and localization data, but effects are from triple-KO so DSK2-specific contribution is not isolated\",\n      \"pmids\": [\"32808330\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deletion of UBL-UBA shuttle proteins including DSK2 results in asynchronous cell division of T. gondii parasites, establishing a role for these proteins in coordinating synchronous cell division.\",\n      \"method\": \"Triple-gene knockout (DDI1, RAD23, DSK2) with cell division phenotype analysis\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell division phenotype observed in triple-KO only, DSK2-specific contribution cannot be attributed individually\",\n      \"pmids\": [\"32808330\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Deletion of UBL-UBA shuttle proteins including DSK2 causes selective accumulation of ubiquitinated proteins in the nucleus and aberrant DNA replication, and leads to mistargeting and accumulation of the virulence effector ROP18, which results in aberrant recruitment of host immunity-related GTPase Irgb6 to the parasitophorous vacuole membrane.\",\n      \"method\": \"Shuttle protein mutant strain analysis, subcellular fractionation/localization of ubiquitinated proteins, ROP18 localization, and host Irgb6 recruitment assay\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic findings from triple-KO; DSK2-specific role cannot be separated from DDI1/RAD23 contributions\",\n      \"pmids\": [\"34727385\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}\n      ]\n    }\n  ],\n  \"current_model\": \"T. gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein that localizes to the cytoplasm and nucleus and functions as part of the ubiquitin-proteasome system to escort ubiquitinylated proteins to the proteasome for degradation, with loss of DSK2 (together with DDI1 and RAD23) causing accumulation of ubiquitinated proteins (particularly in the nucleus), aberrant DNA replication, asynchronous cell division, and mistargeting of the virulence effector ROP18.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Toxoplasma gondii DSK2 (TGGT1_223680) is a UBL-UBA shuttle protein of the ubiquitin-proteasome system that localizes to the cytoplasm and nucleus and functions to escort ubiquitinylated substrates to the proteasome for degradation [#0]. It acts redundantly with the shuttle proteins DDI1 and RAD23: combined loss of the three proteins causes accumulation of ubiquitinylated proteins [#0]. Because all reported mechanistic phenotypes derive from a triple knockout, the individual contribution of DSK2 has not been isolated in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing whether T. gondii encodes functional ubiquitin-shuttle machinery, this work identified DSK2 as a cytoplasmic/nuclear UBL-UBA shuttle protein whose loss (with DDI1 and RAD23) triggers accumulation of ubiquitinylated proteins, placing it in the proteasomal degradation route.\",\n      \"evidence\": \"Triple-gene knockout (DDI1, RAD23, DSK2), subcellular localization, and ubiquitinated-protein accumulation assay in TGGT1\",\n      \"pmids\": [\"32808330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DSK2-specific contribution cannot be separated from DDI1/RAD23 in a triple-KO\",\n        \"no direct substrate of DSK2 identified\",\n        \"no reconstitution of DSK2-proteasome escort in vitro\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Testing whether shuttle-protein function extends beyond proteostasis, deletion of the shuttle proteins including DSK2 produced asynchronous cell division, linking the ubiquitin-shuttle machinery to coordination of synchronous parasite replication.\",\n      \"evidence\": \"Triple-gene knockout (DDI1, RAD23, DSK2) with cell division phenotype analysis in TGGT1\",\n      \"pmids\": [\"32808330\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"phenotype observed only in triple-KO; DSK2-specific role not attributed\",\n        \"mechanism linking shuttle function to division timing unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Probing the downstream consequences of shuttle-protein loss, mutation of the shuttle proteins including DSK2 caused nuclear accumulation of ubiquitinated proteins, aberrant DNA replication, and mistargeting of the virulence effector ROP18, which in turn led to aberrant host Irgb6 recruitment to the parasitophorous vacuole membrane.\",\n      \"evidence\": \"Shuttle-protein mutant analysis, subcellular localization of ubiquitinated proteins, ROP18 localization, and host Irgb6 recruitment assay in TGGT1\",\n      \"pmids\": [\"34727385\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"findings derive from triple-KO; DSK2-specific role not separable from DDI1/RAD23\",\n        \"mechanistic link between shuttle-protein loss and ROP18 mistargeting not defined\",\n        \"whether DSK2 directly handles ROP18 as a substrate is untested\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific, non-redundant contribution of DSK2 — its direct substrates and how its loss individually affects proteostasis, cell division, and virulence-effector targeting — remains unresolved because all phenotypes to date derive from combined deletion with DDI1 and RAD23.\",\n      \"evidence\": \"No single-gene DSK2 characterization in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no single DSK2 knockout phenotype reported\",\n        \"no DSK2-specific substrate identified\",\n        \"no structural or biochemical characterization of DSK2 UBL/UBA domains\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031593\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]},\n      {\"term_id\": \"GO:0043130\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]},\n      {\"term_id\": \"GO:0051301\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"TGGT1\"}]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DDI1\", \"RAD23\"],\n    \"other_free_text\": [\n      \"Loss of the DSK2/DDI1/RAD23 shuttle proteins causes mistargeting of the virulence effector ROP18 and aberrant host Irgb6 recruitment to the parasitophorous vacuole membrane [#2].\",\n      \"All reported DSK2 phenotypes derive from triple knockout with DDI1 and RAD23; DSK2-specific contribution has not been isolated.\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_223680","name":"DSK2","product":"ubiquitin domain-containing protein DSK2","uniprot_acc":"A0A125YP03","chromosome":"TGME49_chrX","start_pos":3657425},{"strain":"GT1","gene_id":"TGGT1_223680","name":null,"product":"ubiquitin family protein","uniprot_acc":null,"chromosome":"TGGT1_chrX","start_pos":3562244},{"strain":"RH88","gene_id":"TGRH88_043460","name":null,"product":"ubiquitin family protein","uniprot_acc":null,"chromosome":"CM023091","start_pos":3903042},{"strain":"VEG","gene_id":"TGVEG_223680","name":null,"product":"ubiquitin family protein","uniprot_acc":"B6KDY1","chromosome":"TGVEG_chrX","start_pos":3561833}]}