{"gene":"IMP4","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"IMP4 protein is a component of the eukaryotic U3 snoRNP complex, and archaeal homologs exist in all archaeal genomes, defining the Imp4/Brix superfamily characterized by a conserved Imp4 signature pattern.","method":"Bioinformatic sequence analysis identifying homologs across archaeal genomes and relating them to four other protein families","journal":"Trends in biochemical sciences","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of function","pmids":["11246005"],"is_preprint":false},{"year":2004,"finding":"Imp4p interacts with Mpp10p within the SSU processome, and this interaction is required for proper pre-rRNA processing (cleavages needed for 18S rRNA biogenesis). Mutations in the N-terminal coiled-coil domain of Imp4p confer cold sensitivity, while C-terminal mutations confer temperature sensitivity for growth and pre-rRNA processing. However, Imp4p mutants that disrupt the Mpp10p-Imp4p two-hybrid interaction are not measurably defective for interaction with Mpp10p in the context of the intact SSU processome, suggesting other complex members stabilize this interaction.","method":"Reverse two-hybrid screen to isolate interaction-defective Imp4p mutants; complementation of imp4 disruption strains; pre-rRNA processing assays; domain swapping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (two-hybrid, complementation, pre-rRNA processing) in a single focused study on Imp4p function","pmids":["14990745"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the archaeal Imp4/Brix superfamily protein Mil (Mth680) reveals that the N- and C-terminal halves share structural similarity to one another (suggesting an ancestral duplication), and both halves adopt the same fold as the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases. The charge distribution and concave surface suggest RNA binding along the N-terminal beta-sheet and a central alpha-helix. The structure rules out a previously proposed helix-turn-helix motif as the RNA-binding moiety.","method":"X-ray crystallography (crystal structure determination) of archaeal Imp4/Brix domain protein with structural comparison","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with structural validation and functional inference; rules out a competing model; rigorous single-study with structural data","pmids":["15654320"],"is_preprint":false},{"year":2006,"finding":"The Schistosoma mansoni IMP4 homolog (SmIMP4) functionally complements an S. cerevisiae imp4 truncation mutant for MMS sensitivity, demonstrating functional conservation of IMP4 across eukaryotes. The yeast imp4 truncation mutant is sensitive to the alkylating agent MMS (methyl methanesulfonate), linking IMP4 to DNA repair/tolerance in addition to RNA metabolism.","method":"Functional complementation in yeast (haploid imp4 truncation mutant) treated with DNA-damaging agents; cross-species complementation with S. mansoni cDNA","journal":"Experimental parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic complementation with clear phenotypic readout (MMS sensitivity), but single lab, partial complementation only, and the DNA repair role is unexpected and not mechanistically resolved","pmids":["17189633"],"is_preprint":false},{"year":2011,"finding":"Loading of Imp4 onto nascent pre-rRNA occurs independently of the Rrp5/UTP-C subcomplex and downstream of the tUTP and U3 snoRNP/UTP-B subcomplexes, placing Imp4 in the assembly hierarchy of the 90S pre-ribosome (SSU processome). Imp4 assembly is thus part of a secondary assembly step that follows the initial tUTP and U3/UTP-B branches.","method":"Chromatin immunoprecipitation of pre-rRNA components combined with depletion of specific subunits (Rrp5, UTP-B components) to dissect assembly order; analysis in S. cerevisiae","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis-based assembly hierarchy established by systematic subunit depletion and pre-rRNA association assays, single lab but multiple assembly conditions tested","pmids":["21724601"],"is_preprint":false},{"year":2019,"finding":"Sas10/Utp3 determines the nucleolar localization of the Mpp10-Imp3-Imp4 complex by interacting with Mpp10. Sas10 protects Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site on Mpp10, and Def interacts with Sas10 to form a Def-Sas10-Mpp10 complex that facilitates Capn3-mediated Mpp10 cleavage. Without Sas10, the Mpp10-Imp3-Imp4 complex fails to localize to the nucleolus.","method":"Zebrafish genetic knockdown/knockout; co-immunoprecipitation; subcellular localization by fluorescence imaging; biochemical fractionation; rescue experiments in zebrafish","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct localization imaging, genetic loss-of-function with clear phenotype, and multiple orthogonal approaches in a single rigorous study","pmids":["30773582"],"is_preprint":false},{"year":2021,"finding":"DDX10 knockdown reduces IMP4 expression, and IMP4 overexpression rescues the anti-proliferative and pro-apoptotic effects of DDX10 knockdown in A549 lung cancer cells, placing IMP4 downstream of DDX10 in a pathway regulating lung cancer cell proliferation.","method":"shRNA knockdown of DDX10; overexpression of IMP4; cell proliferation and apoptosis assays in vitro and xenograft in vivo","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — rescue experiment establishes epistatic relationship but the molecular mechanism linking DDX10 to IMP4 is not defined; single lab, no direct biochemical interaction shown","pmids":["33973712"],"is_preprint":false},{"year":2022,"finding":"IMP4 silencing in lung adenocarcinoma cells suppresses proliferation, migration, invasion, and glycolysis, promotes apoptosis, and induces cell cycle arrest, associated with inactivation of ERK signaling. ERK pathway inhibition (SCH772984) phenocopies IMP4 silencing, and IMP4 overexpression-induced effects are reversed by the ERK inhibitor, placing IMP4 upstream of ERK in LUAD cells.","method":"siRNA/shRNA knockdown and overexpression of IMP4 in LUAD cell lines; ERK pathway inhibitor rescue; CCK-8, EdU, flow cytometry, wound healing, Transwell assays; mouse xenograft model; Western blotting","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis via pharmacological inhibitor rescue, but no direct biochemical mechanism linking IMP4 (a ribosome biogenesis factor) to ERK is established; single lab","pmids":["36317123"],"is_preprint":false}],"current_model":"IMP4 is a conserved component of the SSU processome (90S pre-ribosome) that forms a stable complex with Mpp10 and Imp3; its loading onto nascent pre-rRNA occurs downstream of the tUTP and U3/UTP-B assembly branches and is dependent on Sas10-mediated delivery of the Mpp10-Imp3-Imp4 complex to the nucleolus, where it is required for pre-rRNA processing and 18S rRNA biogenesis; the Imp4/Brix domain adopts a fold related to the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases and likely mediates RNA binding through a concave surface on its N-terminal half."},"narrative":{"mechanistic_narrative":"IMP4 is a conserved component of the small subunit (SSU) processome (90S pre-ribosome) required for pre-rRNA processing and 18S rRNA biogenesis [PMID:14990745]. Within this particle it functions as part of a stable Mpp10-Imp3-Imp4 module, and its physical interaction with Mpp10 is required for the cleavages that generate 18S rRNA [PMID:14990745]. Loading of Imp4 onto nascent pre-rRNA occurs as a secondary assembly step, downstream of the tUTP and U3 snoRNP/UTP-B branches and independently of the Rrp5/UTP-C subcomplex [PMID:21724601], and nucleolar delivery of the Mpp10-Imp3-Imp4 complex depends on Sas10/Utp3, which targets the module to the nucleolus through its interaction with Mpp10 [PMID:30773582]. The protein belongs to the Imp4/Brix superfamily, whose domain adopts a fold related to the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases and presents a concave, charged surface predicted to mediate RNA binding [PMID:15654320]. Beyond its role in ribosome biogenesis, IMP4 has been linked to proliferation and survival in lung adenocarcinoma cells [PMID:33973712, PMID:36317123], but the molecular mechanism connecting this ribosome biogenesis factor to those phenotypes has not been characterized in the available corpus.","teleology":[{"year":2001,"claim":"Established that IMP4 is a U3 snoRNP component conserved from archaea to eukaryotes and defined the Imp4/Brix superfamily, framing IMP4 as a ribosome biogenesis factor with an ancient origin.","evidence":"Bioinformatic sequence analysis across archaeal and eukaryotic genomes identifying a conserved Imp4 signature","pmids":["11246005"],"confidence":"Low","gaps":["Computational only — no direct experimental validation of function","Does not establish biochemical activity or binding partners","Role of the conserved domain in RNA binding not tested"]},{"year":2004,"claim":"Showed that Imp4p physically interacts with Mpp10p in the SSU processome and that this interaction is required for the pre-rRNA cleavages generating 18S rRNA, placing IMP4 functionally within the processing machinery.","evidence":"Reverse two-hybrid screen for interaction-defective mutants, complementation of imp4 disruption strains, domain swapping and pre-rRNA processing assays in S. cerevisiae","pmids":["14990745"],"confidence":"Medium","gaps":["Interaction-defective mutants were not measurably defective in the intact processome, indicating other members stabilize the contact","Direct RNA targets of Imp4p not mapped","Structural basis of the Mpp10p interaction unknown"]},{"year":2005,"claim":"Determined the structure of the Imp4/Brix domain, revealing an internal duplication and a fold matching the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases, and identified the likely RNA-binding surface while ruling out a previously proposed helix-turn-helix motif.","evidence":"X-ray crystallography of the archaeal Imp4/Brix protein Mil (Mth680) with structural comparison","pmids":["15654320"],"confidence":"High","gaps":["RNA-binding surface inferred from charge/shape, not from a protein-RNA co-structure","Structure is of an archaeal homolog, not the eukaryotic IMP4 in the processome","Functional contribution of the duplicated halves untested"]},{"year":2006,"claim":"Demonstrated functional conservation of IMP4 across eukaryotes via cross-species complementation and unexpectedly linked the yeast mutant to alkylation-damage sensitivity.","evidence":"Functional complementation of a yeast imp4 truncation mutant with S. mansoni cDNA using MMS sensitivity as readout","pmids":["17189633"],"confidence":"Medium","gaps":["Complementation only partial","Mechanistic basis of the DNA-damage/MMS link not resolved","Single lab; whether the DNA repair phenotype is direct or secondary to ribosome biogenesis defects unclear"]},{"year":2011,"claim":"Placed IMP4 in the SSU processome assembly hierarchy, showing its loading is a secondary step downstream of the tUTP and U3/UTP-B branches and independent of Rrp5/UTP-C.","evidence":"ChIP of pre-rRNA components combined with subunit depletion to dissect assembly order in S. cerevisiae","pmids":["21724601"],"confidence":"Medium","gaps":["Does not define the molecular signal triggering Imp4 loading","Order relative to all processome components not fully resolved","Single lab, epistasis-based inference"]},{"year":2019,"claim":"Identified Sas10/Utp3 as the determinant of nucleolar localization for the Mpp10-Imp3-Imp4 complex, defining how the module is delivered to its site of action and protected from proteolysis.","evidence":"Zebrafish loss-of-function genetics, reciprocal co-immunoprecipitation, localization imaging and rescue experiments","pmids":["30773582"],"confidence":"High","gaps":["Whether IMP4 itself contacts Sas10 directly versus via Mpp10 not separated","Regulation of the Def-Sas10-Mpp10/Capn3 cleavage axis in mammalian cells untested","Consequence of mislocalization specifically for IMP4 function not isolated"]},{"year":2021,"claim":"Placed IMP4 downstream of DDX10 in a pathway promoting lung cancer cell proliferation, with IMP4 overexpression rescuing DDX10-knockdown phenotypes.","evidence":"shRNA knockdown of DDX10 and IMP4 overexpression rescue in A549 cells, with xenograft validation","pmids":["33973712"],"confidence":"Low","gaps":["No direct biochemical interaction between DDX10 and IMP4 shown","Molecular mechanism linking DDX10 to IMP4 expression undefined","Single cell line / single lab"]},{"year":2022,"claim":"Linked IMP4 to ERK signaling in lung adenocarcinoma, with IMP4 silencing suppressing proliferation, migration and glycolysis and ERK inhibition phenocopying and reversing IMP4 effects.","evidence":"siRNA/shRNA and overexpression with ERK inhibitor rescue, proliferation/migration/glycolysis assays and xenografts in LUAD models","pmids":["36317123"],"confidence":"Low","gaps":["No direct biochemical mechanism connecting a ribosome biogenesis factor to ERK established","Whether the oncogenic effect reflects ribosome biogenesis or a separate function unresolved","Single lab; epistasis via pharmacological inhibitor only"]},{"year":null,"claim":"How IMP4 contributes to pre-rRNA recognition and cleavage at atomic resolution within the human SSU processome, and whether its reported roles in DNA-damage tolerance and ERK-driven proliferation are direct or downstream consequences of disrupted ribosome biogenesis, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No protein-RNA co-structure of eukaryotic IMP4 in the processome","Mechanistic basis of non-ribosomal phenotypes (MMS sensitivity, ERK, DDX10) undefined","Direct RNA substrates and cleavage role of IMP4 not biochemically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4]}],"complexes":["SSU processome (90S pre-ribosome)","U3 snoRNP","Mpp10-Imp3-Imp4 complex"],"partners":["MPHOSPH10","IMP3","UTP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCT7","full_name":"Signal peptide peptidase-like 2B","aliases":["Intramembrane protease 4","IMP-4","Presenilin homologous protein 4","PSH4","Presenilin-like protein 1"],"length_aa":592,"mass_kda":64.6,"function":"Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in ITM2B and TNF processing (PubMed:16829951, PubMed:16829952, PubMed:17965014, PubMed:19114711, PubMed:22194595). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829951, PubMed:16829952). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus processed leader peptide gp18 of the envelope glycoprotein gp130 dependently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852)","subcellular_location":"Cell membrane; Golgi apparatus membrane; Lysosome membrane; Endosome membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCT7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IMP4","classification":"Common Essential","n_dependent_lines":1197,"n_total_lines":1208,"dependency_fraction":0.9908940397350994},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MPHOSPH10","stoichiometry":4.0},{"gene":"IMP3","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IMP4","total_profiled":1310},"omim":[{"mim_id":"612981","title":"IMP U3 SMALL NUCLEOLAR RIBONUCLEAR PROTEIN 4; IMP4","url":"https://www.omim.org/entry/612981"},{"mim_id":"612980","title":"IMP U3 SMALL NUCLEOLAR RIBONUCLEAR PROTEIN 3; IMP3","url":"https://www.omim.org/entry/612980"},{"mim_id":"608239","title":"SIGNAL PEPTIDE PEPTIDASE-LIKE 2B; SPPL2B","url":"https://www.omim.org/entry/608239"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IMP4"},"hgnc":{"alias_symbol":["MGC19606","BXDC4"],"prev_symbol":[]},"alphafold":{"accession":"Q8TCT7","domains":[{"cath_id":"3.50.30.30","chopping":"29-165","consensus_level":"high","plddt":85.9964,"start":29,"end":165},{"cath_id":"-","chopping":"174-207_220-284_293-501","consensus_level":"medium","plddt":85.7526,"start":174,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCT7-F1-predicted_aligned_error_v6.png","plddt_mean":76.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IMP4","jax_strain_url":"https://www.jax.org/strain/search?query=IMP4"},"sequence":{"accession":"Q8TCT7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCT7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCT7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCT7"}},"corpus_meta":[{"pmid":"11181348","id":"PMC_11181348","title":"IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998.","date":"2001","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/11181348","citation_count":189,"is_preprint":false},{"pmid":"11150665","id":"PMC_11150665","title":"Occurrence of a new metallo-beta-lactamase IMP-4 carried on a conjugative plasmid in Citrobacter youngae from the People's Republic of China.","date":"2001","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11150665","citation_count":88,"is_preprint":false},{"pmid":"17284537","id":"PMC_17284537","title":"IMP-4 and OXA beta-lactamases in Acinetobacter baumannii from Singapore.","date":"2007","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/17284537","citation_count":76,"is_preprint":false},{"pmid":"27767038","id":"PMC_27767038","title":"Isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from cats.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27767038","citation_count":62,"is_preprint":false},{"pmid":"26282422","id":"PMC_26282422","title":"Emergence of Raoultella ornithinolytica coproducing IMP-4 and KPC-2 carbapenemases in China.","date":"2015","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/26282422","citation_count":50,"is_preprint":false},{"pmid":"21724601","id":"PMC_21724601","title":"Elucidation of the assembly events required for the recruitment of Utp20, Imp4 and Bms1 onto nascent pre-ribosomes.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21724601","citation_count":47,"is_preprint":false},{"pmid":"34704778","id":"PMC_34704778","title":"Emergence of Tigecycline Nonsusceptible and IMP-4 Carbapenemase-Producing K2-ST65 Hypervirulent Klebsiella pneumoniae in China.","date":"2021","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/34704778","citation_count":35,"is_preprint":false},{"pmid":"30773582","id":"PMC_30773582","title":"Sas10 controls ribosome biogenesis by stabilizing Mpp10 and delivering the Mpp10-Imp3-Imp4 complex to nucleolus.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30773582","citation_count":28,"is_preprint":false},{"pmid":"22271301","id":"PMC_22271301","title":"Characterization of a novel Klebsiella pneumoniae sequence type 476 carrying both bla KPC-2 and bla IMP-4.","date":"2012","source":"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22271301","citation_count":28,"is_preprint":false},{"pmid":"35225687","id":"PMC_35225687","title":"Phenotypic and Genotypic Characterization of a Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae ST17-KL38 Clinical Isolate Harboring the Carbapenemase IMP-4.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/35225687","citation_count":25,"is_preprint":false},{"pmid":"33217119","id":"PMC_33217119","title":"Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review.","date":"2020","source":"Transplant infectious disease : an official journal of the Transplantation Society","url":"https://pubmed.ncbi.nlm.nih.gov/33217119","citation_count":24,"is_preprint":false},{"pmid":"25428154","id":"PMC_25428154","title":"A case of IMP-4-, OXA-421-, OXA-96-, and CARB-2-producing Acinetobacter pittii sequence type 119 in Australia.","date":"2014","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25428154","citation_count":21,"is_preprint":false},{"pmid":"29229976","id":"PMC_29229976","title":"A novel Tn1696-like composite transposon (Tn6404) harboring bla IMP-4 in a Klebsiella pneumoniae isolate carrying a rare ESBL gene bla SFO-1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29229976","citation_count":21,"is_preprint":false},{"pmid":"19748427","id":"PMC_19748427","title":"Combination of IMP-4 metallo-beta-lactamase production and porin deficiency causes carbapenem resistance in a Klebsiella oxytoca clinical isolate.","date":"2009","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/19748427","citation_count":19,"is_preprint":false},{"pmid":"33973712","id":"PMC_33973712","title":"DDX10 promotes human lung carcinoma proliferation by U3 small nucleolar ribonucleoprotein IMP4.","date":"2021","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33973712","citation_count":17,"is_preprint":false},{"pmid":"14990745","id":"PMC_14990745","title":"Two-hybrid Mpp10p interaction-defective Imp4 proteins are not interaction defective in vivo but do confer specific pre-rRNA processing defects in Saccharomyces cerevisiae.","date":"2004","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/14990745","citation_count":17,"is_preprint":false},{"pmid":"20462725","id":"PMC_20462725","title":"Metallo-beta-lactamase-producing imipenem-resistant Pseudomonas aeruginosa clinical isolates in a university teaching hospital in Malaysia: detection of IMP-7 and first identification of IMP-4, VIM-2, and VIM-11.","date":"2010","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/20462725","citation_count":17,"is_preprint":false},{"pmid":"11246005","id":"PMC_11246005","title":"The archaeal homolog of the Imp4 protein, a eukaryotic U3 snoRNP component.","date":"2001","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/11246005","citation_count":15,"is_preprint":false},{"pmid":"34659175","id":"PMC_34659175","title":"First Report of bla IMP-4 and bla SRT-2 Coproducing Serratia marcescens Clinical Isolate in China.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34659175","citation_count":15,"is_preprint":false},{"pmid":"24031907","id":"PMC_24031907","title":"Isolation of the first IMP-4 metallo-β-lactamase producing Klebsiella pneumoniae in Tianjin, China.","date":"2012","source":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","url":"https://pubmed.ncbi.nlm.nih.gov/24031907","citation_count":13,"is_preprint":false},{"pmid":"15654320","id":"PMC_15654320","title":"Crystal structure of Mil (Mth680): internal duplication and similarity between the Imp4/Brix domain and the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases.","date":"2005","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/15654320","citation_count":11,"is_preprint":false},{"pmid":"34170219","id":"PMC_34170219","title":"Characterization of a carbapenem-resistant Citrobacter amalonaticus coharbouring bla IMP-4 and qnrs1 genes.","date":"2021","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34170219","citation_count":9,"is_preprint":false},{"pmid":"32341658","id":"PMC_32341658","title":"Complete-Genome Sequencing and Comparative Genomic Characterization of an IMP-4 Producing Citrobacter freundii Isolate from Patient with Diarrhea.","date":"2020","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/32341658","citation_count":8,"is_preprint":false},{"pmid":"36184039","id":"PMC_36184039","title":"Comparative analysis of IMP-4- and OXA-58-containing plasmids of three carbapenemase-producing Acinetobacter ursingii strains in the Netherlands.","date":"2022","source":"Journal of global antimicrobial resistance","url":"https://pubmed.ncbi.nlm.nih.gov/36184039","citation_count":6,"is_preprint":false},{"pmid":"36317123","id":"PMC_36317123","title":"IMP4 Silencing Inhibits the Malignancy of Lung Adenocarcinoma via ERK Pathway.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36317123","citation_count":5,"is_preprint":false},{"pmid":"17189633","id":"PMC_17189633","title":"Schistosoma mansoni: the IMP4 gene is involved in DNA repair/tolerance after treatment with alkylating agent methyl methane sulfonate.","date":"2006","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17189633","citation_count":5,"is_preprint":false},{"pmid":"36389152","id":"PMC_36389152","title":"Detection of IMP-4 and SFO-1 co-producing ST51 Enterobacter hormaechei clinical isolates.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36389152","citation_count":5,"is_preprint":false},{"pmid":"40293254","id":"PMC_40293254","title":"Comparison of CRISPR-Cas9, CRISPR-Cas12f1, and CRISPR-Cas3 in eradicating resistance genes KPC-2 and IMP-4.","date":"2025","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/40293254","citation_count":3,"is_preprint":false},{"pmid":"39973928","id":"PMC_39973928","title":"Genomic characteristics of ST6115 carbapenem-resistant Klebsiella pneumoniae coharboring bla NDM-1 and bla IMP-4.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39973928","citation_count":2,"is_preprint":false},{"pmid":"41972123","id":"PMC_41972123","title":"Integrative multi-omics dissection identifies ACO2, KLF5, and IMP4 as central regulators of the mitochondrial-immune axis in ulcerative colitis.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41972123","citation_count":0,"is_preprint":false},{"pmid":"40904310","id":"PMC_40904310","title":"[Genomic characteristics and mechanisms of horizontal plasmid transfer in Klebsiella pneumoniae producing NDM-1 and IMP-4 carbapenemases].","date":"2025","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/40904310","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19188,"output_tokens":2637,"usd":0.048559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9479,"output_tokens":3236,"usd":0.064147,"stage2_stop_reason":"end_turn"},"total_usd":0.112706,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to classify papers:\n\n- Papers 1-5, 7, 9-10, 12-14, 17, 19-20, 22-24, 27-29, 31: These are about IMP-4 as a **metallo-beta-lactamase** enzyme in bacteria (antimicrobial resistance gene). This is a **symbol collision** — blaIMP-4 is a bacterial carbapenemase, NOT the human/eukaryotic IMP4 gene (U3 snoRNP component involved in ribosome biogenesis).\n\n- Papers 6, 8, 15, 16, 18, 21, 25, 26: These are about the eukaryotic/archaeal IMP4 protein (U3 snoRNP component, ribosome biogenesis). These are relevant.\n\n- Paper 11, 28: About the bacterial resistance gene — EXCLUDE.\n- Paper 30: Multi-omics/GWAS association study — expression correlation only, no mechanistic experiments on IMP4 specifically. EXCLUDE.\n\nLet me extract mechanistic discoveries from papers 6, 8, 15, 16, 18, 21, 25, 26.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IMP4 protein is a component of the eukaryotic U3 snoRNP complex, and archaeal homologs exist in all archaeal genomes, defining the Imp4/Brix superfamily characterized by a conserved Imp4 signature pattern.\",\n      \"method\": \"Bioinformatic sequence analysis identifying homologs across archaeal genomes and relating them to four other protein families\",\n      \"journal\": \"Trends in biochemical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic analysis only, no direct experimental validation of function\",\n      \"pmids\": [\"11246005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Imp4p interacts with Mpp10p within the SSU processome, and this interaction is required for proper pre-rRNA processing (cleavages needed for 18S rRNA biogenesis). Mutations in the N-terminal coiled-coil domain of Imp4p confer cold sensitivity, while C-terminal mutations confer temperature sensitivity for growth and pre-rRNA processing. However, Imp4p mutants that disrupt the Mpp10p-Imp4p two-hybrid interaction are not measurably defective for interaction with Mpp10p in the context of the intact SSU processome, suggesting other complex members stabilize this interaction.\",\n      \"method\": \"Reverse two-hybrid screen to isolate interaction-defective Imp4p mutants; complementation of imp4 disruption strains; pre-rRNA processing assays; domain swapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (two-hybrid, complementation, pre-rRNA processing) in a single focused study on Imp4p function\",\n      \"pmids\": [\"14990745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the archaeal Imp4/Brix superfamily protein Mil (Mth680) reveals that the N- and C-terminal halves share structural similarity to one another (suggesting an ancestral duplication), and both halves adopt the same fold as the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases. The charge distribution and concave surface suggest RNA binding along the N-terminal beta-sheet and a central alpha-helix. The structure rules out a previously proposed helix-turn-helix motif as the RNA-binding moiety.\",\n      \"method\": \"X-ray crystallography (crystal structure determination) of archaeal Imp4/Brix domain protein with structural comparison\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with structural validation and functional inference; rules out a competing model; rigorous single-study with structural data\",\n      \"pmids\": [\"15654320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Schistosoma mansoni IMP4 homolog (SmIMP4) functionally complements an S. cerevisiae imp4 truncation mutant for MMS sensitivity, demonstrating functional conservation of IMP4 across eukaryotes. The yeast imp4 truncation mutant is sensitive to the alkylating agent MMS (methyl methanesulfonate), linking IMP4 to DNA repair/tolerance in addition to RNA metabolism.\",\n      \"method\": \"Functional complementation in yeast (haploid imp4 truncation mutant) treated with DNA-damaging agents; cross-species complementation with S. mansoni cDNA\",\n      \"journal\": \"Experimental parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic complementation with clear phenotypic readout (MMS sensitivity), but single lab, partial complementation only, and the DNA repair role is unexpected and not mechanistically resolved\",\n      \"pmids\": [\"17189633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loading of Imp4 onto nascent pre-rRNA occurs independently of the Rrp5/UTP-C subcomplex and downstream of the tUTP and U3 snoRNP/UTP-B subcomplexes, placing Imp4 in the assembly hierarchy of the 90S pre-ribosome (SSU processome). Imp4 assembly is thus part of a secondary assembly step that follows the initial tUTP and U3/UTP-B branches.\",\n      \"method\": \"Chromatin immunoprecipitation of pre-rRNA components combined with depletion of specific subunits (Rrp5, UTP-B components) to dissect assembly order; analysis in S. cerevisiae\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis-based assembly hierarchy established by systematic subunit depletion and pre-rRNA association assays, single lab but multiple assembly conditions tested\",\n      \"pmids\": [\"21724601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sas10/Utp3 determines the nucleolar localization of the Mpp10-Imp3-Imp4 complex by interacting with Mpp10. Sas10 protects Mpp10 from Capn3-mediated cleavage by masking the Capn3-recognition site on Mpp10, and Def interacts with Sas10 to form a Def-Sas10-Mpp10 complex that facilitates Capn3-mediated Mpp10 cleavage. Without Sas10, the Mpp10-Imp3-Imp4 complex fails to localize to the nucleolus.\",\n      \"method\": \"Zebrafish genetic knockdown/knockout; co-immunoprecipitation; subcellular localization by fluorescence imaging; biochemical fractionation; rescue experiments in zebrafish\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct localization imaging, genetic loss-of-function with clear phenotype, and multiple orthogonal approaches in a single rigorous study\",\n      \"pmids\": [\"30773582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX10 knockdown reduces IMP4 expression, and IMP4 overexpression rescues the anti-proliferative and pro-apoptotic effects of DDX10 knockdown in A549 lung cancer cells, placing IMP4 downstream of DDX10 in a pathway regulating lung cancer cell proliferation.\",\n      \"method\": \"shRNA knockdown of DDX10; overexpression of IMP4; cell proliferation and apoptosis assays in vitro and xenograft in vivo\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — rescue experiment establishes epistatic relationship but the molecular mechanism linking DDX10 to IMP4 is not defined; single lab, no direct biochemical interaction shown\",\n      \"pmids\": [\"33973712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IMP4 silencing in lung adenocarcinoma cells suppresses proliferation, migration, invasion, and glycolysis, promotes apoptosis, and induces cell cycle arrest, associated with inactivation of ERK signaling. ERK pathway inhibition (SCH772984) phenocopies IMP4 silencing, and IMP4 overexpression-induced effects are reversed by the ERK inhibitor, placing IMP4 upstream of ERK in LUAD cells.\",\n      \"method\": \"siRNA/shRNA knockdown and overexpression of IMP4 in LUAD cell lines; ERK pathway inhibitor rescue; CCK-8, EdU, flow cytometry, wound healing, Transwell assays; mouse xenograft model; Western blotting\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis via pharmacological inhibitor rescue, but no direct biochemical mechanism linking IMP4 (a ribosome biogenesis factor) to ERK is established; single lab\",\n      \"pmids\": [\"36317123\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IMP4 is a conserved component of the SSU processome (90S pre-ribosome) that forms a stable complex with Mpp10 and Imp3; its loading onto nascent pre-rRNA occurs downstream of the tUTP and U3/UTP-B assembly branches and is dependent on Sas10-mediated delivery of the Mpp10-Imp3-Imp4 complex to the nucleolus, where it is required for pre-rRNA processing and 18S rRNA biogenesis; the Imp4/Brix domain adopts a fold related to the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases and likely mediates RNA binding through a concave surface on its N-terminal half.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IMP4 is a conserved component of the small subunit (SSU) processome (90S pre-ribosome) required for pre-rRNA processing and 18S rRNA biogenesis [#1]. Within this particle it functions as part of a stable Mpp10-Imp3-Imp4 module, and its physical interaction with Mpp10 is required for the cleavages that generate 18S rRNA [#1]. Loading of Imp4 onto nascent pre-rRNA occurs as a secondary assembly step, downstream of the tUTP and U3 snoRNP/UTP-B branches and independently of the Rrp5/UTP-C subcomplex [#4], and nucleolar delivery of the Mpp10-Imp3-Imp4 complex depends on Sas10/Utp3, which targets the module to the nucleolus through its interaction with Mpp10 [#5]. The protein belongs to the Imp4/Brix superfamily, whose domain adopts a fold related to the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases and presents a concave, charged surface predicted to mediate RNA binding [#2]. Beyond its role in ribosome biogenesis, IMP4 has been linked to proliferation and survival in lung adenocarcinoma cells [#6, #7], but the molecular mechanism connecting this ribosome biogenesis factor to those phenotypes has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that IMP4 is a U3 snoRNP component conserved from archaea to eukaryotes and defined the Imp4/Brix superfamily, framing IMP4 as a ribosome biogenesis factor with an ancient origin.\",\n      \"evidence\": \"Bioinformatic sequence analysis across archaeal and eukaryotic genomes identifying a conserved Imp4 signature\",\n      \"pmids\": [\"11246005\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational only \\u2014 no direct experimental validation of function\",\n        \"Does not establish biochemical activity or binding partners\",\n        \"Role of the conserved domain in RNA binding not tested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that Imp4p physically interacts with Mpp10p in the SSU processome and that this interaction is required for the pre-rRNA cleavages generating 18S rRNA, placing IMP4 functionally within the processing machinery.\",\n      \"evidence\": \"Reverse two-hybrid screen for interaction-defective mutants, complementation of imp4 disruption strains, domain swapping and pre-rRNA processing assays in S. cerevisiae\",\n      \"pmids\": [\"14990745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction-defective mutants were not measurably defective in the intact processome, indicating other members stabilize the contact\",\n        \"Direct RNA targets of Imp4p not mapped\",\n        \"Structural basis of the Mpp10p interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determined the structure of the Imp4/Brix domain, revealing an internal duplication and a fold matching the anticodon-binding domain of class IIa aminoacyl-tRNA synthetases, and identified the likely RNA-binding surface while ruling out a previously proposed helix-turn-helix motif.\",\n      \"evidence\": \"X-ray crystallography of the archaeal Imp4/Brix protein Mil (Mth680) with structural comparison\",\n      \"pmids\": [\"15654320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"RNA-binding surface inferred from charge/shape, not from a protein-RNA co-structure\",\n        \"Structure is of an archaeal homolog, not the eukaryotic IMP4 in the processome\",\n        \"Functional contribution of the duplicated halves untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated functional conservation of IMP4 across eukaryotes via cross-species complementation and unexpectedly linked the yeast mutant to alkylation-damage sensitivity.\",\n      \"evidence\": \"Functional complementation of a yeast imp4 truncation mutant with S. mansoni cDNA using MMS sensitivity as readout\",\n      \"pmids\": [\"17189633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Complementation only partial\",\n        \"Mechanistic basis of the DNA-damage/MMS link not resolved\",\n        \"Single lab; whether the DNA repair phenotype is direct or secondary to ribosome biogenesis defects unclear\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed IMP4 in the SSU processome assembly hierarchy, showing its loading is a secondary step downstream of the tUTP and U3/UTP-B branches and independent of Rrp5/UTP-C.\",\n      \"evidence\": \"ChIP of pre-rRNA components combined with subunit depletion to dissect assembly order in S. cerevisiae\",\n      \"pmids\": [\"21724601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not define the molecular signal triggering Imp4 loading\",\n        \"Order relative to all processome components not fully resolved\",\n        \"Single lab, epistasis-based inference\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Sas10/Utp3 as the determinant of nucleolar localization for the Mpp10-Imp3-Imp4 complex, defining how the module is delivered to its site of action and protected from proteolysis.\",\n      \"evidence\": \"Zebrafish loss-of-function genetics, reciprocal co-immunoprecipitation, localization imaging and rescue experiments\",\n      \"pmids\": [\"30773582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IMP4 itself contacts Sas10 directly versus via Mpp10 not separated\",\n        \"Regulation of the Def-Sas10-Mpp10/Capn3 cleavage axis in mammalian cells untested\",\n        \"Consequence of mislocalization specifically for IMP4 function not isolated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed IMP4 downstream of DDX10 in a pathway promoting lung cancer cell proliferation, with IMP4 overexpression rescuing DDX10-knockdown phenotypes.\",\n      \"evidence\": \"shRNA knockdown of DDX10 and IMP4 overexpression rescue in A549 cells, with xenograft validation\",\n      \"pmids\": [\"33973712\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical interaction between DDX10 and IMP4 shown\",\n        \"Molecular mechanism linking DDX10 to IMP4 expression undefined\",\n        \"Single cell line / single lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked IMP4 to ERK signaling in lung adenocarcinoma, with IMP4 silencing suppressing proliferation, migration and glycolysis and ERK inhibition phenocopying and reversing IMP4 effects.\",\n      \"evidence\": \"siRNA/shRNA and overexpression with ERK inhibitor rescue, proliferation/migration/glycolysis assays and xenografts in LUAD models\",\n      \"pmids\": [\"36317123\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical mechanism connecting a ribosome biogenesis factor to ERK established\",\n        \"Whether the oncogenic effect reflects ribosome biogenesis or a separate function unresolved\",\n        \"Single lab; epistasis via pharmacological inhibitor only\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IMP4 contributes to pre-rRNA recognition and cleavage at atomic resolution within the human SSU processome, and whether its reported roles in DNA-damage tolerance and ERK-driven proliferation are direct or downstream consequences of disrupted ribosome biogenesis, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No protein-RNA co-structure of eukaryotic IMP4 in the processome\",\n        \"Mechanistic basis of non-ribosomal phenotypes (MMS sensitivity, ERK, DDX10) undefined\",\n        \"Direct RNA substrates and cleavage role of IMP4 not biochemically dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"SSU processome (90S pre-ribosome)\",\n      \"U3 snoRNP\",\n      \"Mpp10-Imp3-Imp4 complex\"\n    ],\n    \"partners\": [\n      \"MPHOSPH10\",\n      \"IMP3\",\n      \"UTP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}