Affinage

EIF3M

Eukaryotic translation initiation factor 3 subunit M · UniProt Q7L2H7

Round 2 corrected
Length
374 aa
Mass
42.5 kDa
Annotated
2026-04-28
41 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3M is a PCI-domain subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that is essential for bulk cellular protein synthesis and polysome formation, distinguishing a functionally distinct eIF3 sub-complex from the eIF3e-containing complex (PMID:15904532). Beyond its role in global translation, EIF3M binds specific mRNA 5′UTRs—including those of CAPRIN1 and MTCH2—to post-transcriptionally regulate their expression, coupling translational control to cell proliferation and mitochondrial homeostasis (PMID:33791168, PMID:42023842). EIF3M protein stability is maintained by deubiquitinases UCHL5 and USP34, and its loss perturbs ribosomal protein gene expression and rRNA processing in vivo (PMID:31855834, PMID:33791168, PMID:42023842). In Drosophila, the ortholog Tango7 additionally functions as an apoptosome co-activator that specifies subcellular domains of non-apoptotic caspase activity for cellular remodeling (PMID:23913920, PMID:28928435).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2005 High

    Establishing that eIF3m defines a distinct eIF3 sub-complex essential for bulk mRNA translation resolved the question of whether PCI-domain subunits were functionally interchangeable within eIF3.

    Evidence Genetic deletion, polysome profiling, and ribonomics in fission yeast

    PMID:15904532

    Open questions at the time
    • Mechanism by which eIF3m selects the bulk mRNA pool versus the eIF3e-restricted pool was not determined
    • Whether the two-complex architecture is conserved in mammals was untested
  2. 2010 Medium

    Demonstrating that eIF3m knockdown impairs human cancer cell proliferation and cycle progression through mRNA-specific translational regulation (e.g., MT2A–CDC25A axis) extended eIF3m's mRNA-selective role to mammalian cells.

    Evidence siRNA knockdown, ribonomics, cell cycle/apoptosis assays in HCT-116 cells

    PMID:20838379

    Open questions at the time
    • Direct binding of eIF3m to identified mRNAs was not shown
    • Single cell line with no in vivo validation
  3. 2013 High

    Discovery that Drosophila Tango7 directly stimulates the apoptosome to drive non-apoptotic caspase-dependent cellular remodeling revealed an unexpected translation-independent function for the eIF3m ortholog.

    Evidence Genetic loss-of-function, in vitro caspase reconstitution, C-terminal domain mapping in Drosophila spermatogenesis

    PMID:23913920

    Open questions at the time
    • Whether the apoptosome co-activator function is conserved in mammals was not tested
    • Structural basis of Tango7 C-terminal interaction with the apoptosome is unresolved
  4. 2017 High

    Showing that Tango7 activates cortical dronc independently of canonical adaptor Dark established that eIF3m ortholog defines a spatially distinct, non-apoptotic caspase activation mechanism for tissue remodeling.

    Evidence Genetic epistasis between tango7 and dark mutants, live imaging, cortical caspase and F-actin assays in Drosophila salivary glands

    PMID:28928435

    Open questions at the time
    • Molecular basis of Dark-independent caspase activation by Tango7 is unknown
    • Whether this cortical function requires eIF3 translation activity was not dissected
  5. 2019 High

    In vivo eIF3m knockdown in mouse liver revealed that reduced eIF3m decouples ribosomal protein gene transcription from rRNA processing, linking eIF3m to ribosome biogenesis quality control beyond its direct role in translation initiation.

    Evidence In vivo RNAi, ribosome profiling, proteomics, phosphoproteomics, and rRNA processing analysis in mouse liver

    PMID:31855834

    Open questions at the time
    • Whether rRNA processing perturbation is a direct or indirect consequence of eIF3m loss is unclear
    • mTOR pathway induction seen in vitro was not recapitulated in vivo, leaving the in vitro relevance uncertain
  6. 2021 Medium

    Identification of direct EIF3M binding to the CAPRIN1 5′UTR and stabilization of EIF3M by deubiquitinase UCHL5 established the first molecularly defined mRNA target and upstream stability mechanism for EIF3M in human cells.

    Evidence RNA immunoprecipitation of 5′UTR, reciprocal co-immunoprecipitation of EIF3M–UCHL5, functional rescue, xenograft models in lung adenocarcinoma

    PMID:33791168

    Open questions at the time
    • Structural determinants of EIF3M 5′UTR recognition are undefined
    • Whether UCHL5-mediated stabilization is specific to cancer contexts or generalizable was not addressed
  7. 2026 Medium

    Demonstration that USP34 deubiquitinates EIF3M and that EIF3M binds the MTCH2 5′UTR to sustain mitochondrial function revealed a second deubiquitinase–EIF3M–target mRNA axis, linking EIF3M translational control to mitochondrial homeostasis.

    Evidence Co-IP, GST pull-down, RIP, RNA pull-down, mitochondrial membrane potential and morphology assays in TNBC cells

    PMID:42023842

    Open questions at the time
    • Whether USP34 and UCHL5 act redundantly or in distinct contexts is unknown
    • No structural or transcriptome-wide mapping of EIF3M RNA-binding specificity has been performed
  8. 2026 Medium

    Finding that FAdV-4 ORF1B protein binds the EIF3M C-terminal domain to promote viral replication demonstrated that EIF3M is a host factor co-opted by a pathogen, consistent with its central role in translation initiation.

    Evidence Co-IP/MS, C-terminal domain mapping, overexpression/knockdown in avian cells

    PMID:41637784

    Open questions at the time
    • Non-mammalian virus system; relevance to mammalian viral infections is untested
    • Whether ORF1B binding competes with eIF3 complex assembly or translation function is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A transcriptome-wide map of EIF3M direct RNA targets and the structural basis of its 5′UTR selectivity remain undefined, as does whether the Drosophila apoptosome co-activator function is conserved in mammals.
  • No CLIP-seq or equivalent unbiased RNA-binding map exists for EIF3M
  • Structural mechanism of 5′UTR recognition is unresolved
  • Mammalian relevance of non-apoptotic caspase co-activation is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 5 GO:0003723 RNA binding 4 GO:0005198 structural molecule activity 2
Localization
GO:0005840 ribosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 2
Partners
DARKDRONCUCHL5USP34
Complex memberships
eIF3

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Fission yeast has two distinct eIF3 complexes that share common core subunits but are distinguished by the PCI proteins eIF3e and eIF3m. eIF3m is an essential gene required for global cellular protein synthesis and polysome formation, unlike eIF3e. Using a ribonomic approach, the eIF3m complex was shown to associate with the bulk of cellular mRNAs, whereas the eIF3e complex associates with a far more restricted mRNA set, indicating that PCI proteins eIF3e and eIF3m define distinct eIF3 complexes that assist in translation of different mRNA sets. Genetic deletion (eif3m essential vs. eif3e non-essential), polysome analysis, ribonomics/microarray with RT-PCR validation, biochemical fractionation BMC biology High 15904532
2010 In human colon cancer cells (HCT-116), siRNA-mediated silencing of eIF3m impairs cell proliferation, cell cycle progression, and induces cell death. Ribonomics identified a subset of eIF3m-associated mRNAs including MIF and MT2A; eIF3m knockdown reduced expression of MT2A downstream effector CDC25A, linking eIF3m to cell cycle control via mRNA-specific translational regulation. siRNA knockdown, cell proliferation/cell cycle/apoptosis assays, ribonomics approach (mRNA immunoprecipitation), RT-PCR validation Oncogene Medium 20838379
2013 Drosophila Tango7 (ortholog of EIF3M) collaborates with the Drosophila apoptosome to drive caspase-dependent cellular remodeling required to resolve individual sperm from a syncytium. Tango7 localizes to the active apoptosome compartment via its C terminus and directly stimulates the activity of this complex in vitro, specifying the apoptosome as an effector of cellular remodeling rather than cell death. Genetic loss-of-function, in vitro caspase activity assay, C-terminal domain truncation/localization analysis, co-localization imaging Genes & development High 23913920
2017 Drosophila Tango7 (EIF3M ortholog) regulates cortical caspase (dronc) activity in living salivary glands independently of the canonical Apaf-1 adaptor Dark. Tango7-dependent cortical dronc activity enables F-actin dismantling at the cortex, allowing glands to stretch as they accumulate secreted products, demonstrating that Tango7 and Dark define mutually exclusive subcellular domains of caspase activity. Genetic loss-of-function (tango7 and dark mutants), live imaging, F-actin staining, cortical caspase activity assays Nature communications High 28928435
2019 In vivo RNAi-mediated knockdown of eIF3m in mouse liver causes transcriptional upregulation of ribosomal protein genes and inhibition of rRNA processing (decoupling rRNA synthesis from ribosomal protein gene transcription), with broad metabolic gene expression changes but few detectable differences in translation of specific mRNAs. In vitro, reduced eIF3m protein levels are associated with induction of the mTOR pathway, an effect not observed in vivo. In vivo RNAi knockdown, transcriptome sequencing, ribosome profiling, whole proteome and phosphoproteome mass spectrometry, rRNA processing analysis Molecular therapy. Nucleic acids High 31855834
2021 EIF3m binds directly to the 5'UTR of CAPRIN1 mRNA and positively regulates its expression at the post-transcriptional level. EIF3m protein stability in lung adenocarcinoma cells is maintained through interaction with the deubiquitinase UCHL5, which stabilizes EIF3m via deubiquitination. The UCHL5/EIF3m/CAPRIN1 axis promotes malignant phenotypes in vitro and in vivo. RNA immunoprecipitation (RIP) of 5'UTR, co-immunoprecipitation (EIF3m-UCHL5 interaction), gain- and loss-of-function assays, in vivo xenograft models American journal of cancer research Medium 33791168
2026 USP34 deubiquitinase maintains EIF3m protein stability through deubiquitination in TNBC cells. EIF3m in turn binds directly to the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function (membrane potential and network structure). Disruption of this USP34/eIF3m/MTCH2 axis impairs mitochondrial function and inhibits TNBC cell proliferation. Co-immunoprecipitation, GST pull-down, RNA immunoprecipitation, RNA pull-down, JC-1 mitochondrial membrane potential assay, MitoSOX/MitoTracker imaging, siRNA knockdown Journal of histotechnology Medium 42023842
2026 EIF3m, particularly its C-terminal domain, physically interacts with ORF1B, a non-structural protein of fowl adenovirus serotype 4 (FAdV-4), as identified by co-immunoprecipitation/mass spectrometry. The two proteins co-localize in the cytoplasm. Overexpression of EIF3m promotes FAdV-4 replication while EIF3m knockdown suppresses it, indicating that the virus hijacks EIF3m to facilitate replication. Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), domain mapping (C-terminal truncation), co-localization imaging, overexpression and knockdown functional assays Poultry science Medium 41637784

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science (New York, N.Y.) 653 32680882
2018 mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 617 30232453
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2015 eIF3 targets cell-proliferation messenger RNAs for translational activation or repression. Nature 340 25849773
2006 eIF3: a versatile scaffold for translation initiation complexes. Trends in biochemical sciences 318 16920360
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2012 MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. Science (New York, N.Y.) 230 22678362
2018 Mapping the Genetic Landscape of Human Cells. Cell 225 30033366
2005 PCI proteins eIF3e and eIF3m define distinct translation initiation factor 3 complexes. BMC biology 120 15904532
2010 eIF3m expression influences the regulation of tumorigenesis-related genes in human colon cancer. Oncogene 45 20838379
2017 Tango7 regulates cortical activity of caspases during reaper-triggered changes in tissue elasticity. Nature communications 26 28928435
2013 Tango7 directs cellular remodeling by the Drosophila apoptosome. Genes & development 26 23913920
2021 EIF3m promotes the malignant phenotype of lung adenocarcinoma by the up-regulation of oncogene CAPRIN1. American journal of cancer research 17 33791168
2020 Roles of eIF3m in the tumorigenesis of triple negative breast cancer. Cancer cell international 14 32368187
2019 In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation. Molecular therapy. Nucleic acids 13 31855834
2024 Exploring the role of eIF3m in prostate cancer: regulation of c-Myc signaling pathway and therapeutic implications. Neoplasma 1 39556433
2026 eIF3m promotes fowl adenovirus serotype 4 replication via interacting with ORF1B protein. Poultry science 0 41637784
2026 USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis. Journal of histotechnology 0 42023842
2004 Chemical heterogeneity of a crystal built of nanoscale coherently twinned Yb(2-x)(Fe,Ga)(17+2x) polytypes. Chemistry (Weinheim an der Bergstrasse, Germany) 0 15214079