Affinage

IMP4

Signal peptide peptidase-like 2B · UniProt Q8TCT7

Length
592 aa
Mass
64.6 kDa
Annotated
2026-06-10
31 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 Low

    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

    PMID:11246005

    Open questions at the time
    • 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
  2. 2004 Medium

    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

    PMID:14990745

    Open questions at the time
    • 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
  3. 2005 High

    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

    PMID:15654320

    Open questions at the time
    • 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
  4. 2006 Medium

    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

    PMID:17189633

    Open questions at the time
    • 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
  5. 2011 Medium

    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

    PMID:21724601

    Open questions at the time
    • Does not define the molecular signal triggering Imp4 loading
    • Order relative to all processome components not fully resolved
    • Single lab, epistasis-based inference
  6. 2019 High

    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

    PMID:30773582

    Open questions at the time
    • 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
  7. 2021 Low

    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

    PMID:33973712

    Open questions at the time
    • No direct biochemical interaction between DDX10 and IMP4 shown
    • Molecular mechanism linking DDX10 to IMP4 expression undefined
    • Single cell line / single lab
  8. 2022 Low

    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

    PMID:36317123

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 1
Localization
GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
IMP3MPHOSPH10UTP3
Complex memberships
Mpp10-Imp3-Imp4 complexSSU processome (90S pre-ribosome)U3 snoRNP

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Bioinformatic sequence analysis identifying homologs across archaeal genomes and relating them to four other protein families Trends in biochemical sciences Low 11246005
2004 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. Reverse two-hybrid screen to isolate interaction-defective Imp4p mutants; complementation of imp4 disruption strains; pre-rRNA processing assays; domain swapping Nucleic acids research Medium 14990745
2005 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. X-ray crystallography (crystal structure determination) of archaeal Imp4/Brix domain protein with structural comparison EMBO reports High 15654320
2006 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. Functional complementation in yeast (haploid imp4 truncation mutant) treated with DNA-damaging agents; cross-species complementation with S. mansoni cDNA Experimental parasitology Medium 17189633
2011 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. Chromatin immunoprecipitation of pre-rRNA components combined with depletion of specific subunits (Rrp5, UTP-B components) to dissect assembly order; analysis in S. cerevisiae Nucleic acids research Medium 21724601
2019 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. Zebrafish genetic knockdown/knockout; co-immunoprecipitation; subcellular localization by fluorescence imaging; biochemical fractionation; rescue experiments in zebrafish Nucleic acids research High 30773582
2021 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. shRNA knockdown of DDX10; overexpression of IMP4; cell proliferation and apoptosis assays in vitro and xenograft in vivo Thoracic cancer Low 33973712
2022 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. 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 of oncology Low 36317123

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998. Antimicrobial agents and chemotherapy 189 11181348
2001 Occurrence of a new metallo-beta-lactamase IMP-4 carried on a conjugative plasmid in Citrobacter youngae from the People's Republic of China. FEMS microbiology letters 88 11150665
2007 IMP-4 and OXA beta-lactamases in Acinetobacter baumannii from Singapore. The Journal of antimicrobial chemotherapy 76 17284537
2016 Isolation and plasmid characterization of carbapenemase (IMP-4) producing Salmonella enterica Typhimurium from cats. Scientific reports 62 27767038
2015 Emergence of Raoultella ornithinolytica coproducing IMP-4 and KPC-2 carbapenemases in China. Antimicrobial agents and chemotherapy 50 26282422
2011 Elucidation of the assembly events required for the recruitment of Utp20, Imp4 and Bms1 onto nascent pre-ribosomes. Nucleic acids research 47 21724601
2021 Emergence of Tigecycline Nonsusceptible and IMP-4 Carbapenemase-Producing K2-ST65 Hypervirulent Klebsiella pneumoniae in China. Microbiology spectrum 35 34704778
2019 Sas10 controls ribosome biogenesis by stabilizing Mpp10 and delivering the Mpp10-Imp3-Imp4 complex to nucleolus. Nucleic acids research 28 30773582
2012 Characterization of a novel Klebsiella pneumoniae sequence type 476 carrying both bla KPC-2 and bla IMP-4. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 28 22271301
2022 Phenotypic and Genotypic Characterization of a Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae ST17-KL38 Clinical Isolate Harboring the Carbapenemase IMP-4. Microbiology spectrum 25 35225687
2020 Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review. Transplant infectious disease : an official journal of the Transplantation Society 24 33217119
2017 A novel Tn1696-like composite transposon (Tn6404) harboring bla IMP-4 in a Klebsiella pneumoniae isolate carrying a rare ESBL gene bla SFO-1. Scientific reports 21 29229976
2014 A case of IMP-4-, OXA-421-, OXA-96-, and CARB-2-producing Acinetobacter pittii sequence type 119 in Australia. Journal of clinical microbiology 21 25428154
2009 Combination of IMP-4 metallo-beta-lactamase production and porin deficiency causes carbapenem resistance in a Klebsiella oxytoca clinical isolate. Diagnostic microbiology and infectious disease 19 19748427
2021 DDX10 promotes human lung carcinoma proliferation by U3 small nucleolar ribonucleoprotein IMP4. Thoracic cancer 17 33973712
2010 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. Diagnostic microbiology and infectious disease 17 20462725
2004 Two-hybrid Mpp10p interaction-defective Imp4 proteins are not interaction defective in vivo but do confer specific pre-rRNA processing defects in Saccharomyces cerevisiae. Nucleic acids research 17 14990745
2021 First Report of bla IMP-4 and bla SRT-2 Coproducing Serratia marcescens Clinical Isolate in China. Frontiers in microbiology 15 34659175
2001 The archaeal homolog of the Imp4 protein, a eukaryotic U3 snoRNP component. Trends in biochemical sciences 15 11246005
2012 Isolation of the first IMP-4 metallo-β-lactamase producing Klebsiella pneumoniae in Tianjin, China. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] 13 24031907
2005 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. EMBO reports 11 15654320
2021 Characterization of a carbapenem-resistant Citrobacter amalonaticus coharbouring bla IMP-4 and qnrs1 genes. Journal of medical microbiology 9 34170219
2020 Complete-Genome Sequencing and Comparative Genomic Characterization of an IMP-4 Producing Citrobacter freundii Isolate from Patient with Diarrhea. Infection and drug resistance 8 32341658
2022 Comparative analysis of IMP-4- and OXA-58-containing plasmids of three carbapenemase-producing Acinetobacter ursingii strains in the Netherlands. Journal of global antimicrobial resistance 6 36184039
2022 IMP4 Silencing Inhibits the Malignancy of Lung Adenocarcinoma via ERK Pathway. Journal of oncology 5 36317123
2022 Detection of IMP-4 and SFO-1 co-producing ST51 Enterobacter hormaechei clinical isolates. Frontiers in cellular and infection microbiology 5 36389152
2006 Schistosoma mansoni: the IMP4 gene is involved in DNA repair/tolerance after treatment with alkylating agent methyl methane sulfonate. Experimental parasitology 5 17189633
2025 Comparison of CRISPR-Cas9, CRISPR-Cas12f1, and CRISPR-Cas3 in eradicating resistance genes KPC-2 and IMP-4. Microbiology spectrum 3 40293254
2025 Genomic characteristics of ST6115 carbapenem-resistant Klebsiella pneumoniae coharboring bla NDM-1 and bla IMP-4. Frontiers in microbiology 2 39973928
2026 Integrative multi-omics dissection identifies ACO2, KLF5, and IMP4 as central regulators of the mitochondrial-immune axis in ulcerative colitis. Frontiers in immunology 0 41972123
2025 [Genomic characteristics and mechanisms of horizontal plasmid transfer in Klebsiella pneumoniae producing NDM-1 and IMP-4 carbapenemases]. Zhonghua yi xue za zhi 0 40904310

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