Affinage

EIF3L

Eukaryotic translation initiation factor 3 subunit L · UniProt Q9Y262

Round 2 corrected
Length
564 aa
Mass
66.7 kDa
Annotated
2026-04-28
61 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3L is an accessory subunit of the eukaryotic translation initiation factor 3 (eIF3) complex that, together with eIF3k, forms an mRNA-selective regulatory module controlling ribosome biogenesis by repressing translation of the ribosomal protein mRNA RPS15A (PMID:37155573). Although dispensable for bulk translation initiation activity in reconstituted assays (PMID:23063735), eIF3L loss enhances global translation, cell proliferation, tumor growth, and stress resistance; in C. elegans, eif-3.L loss-of-function extends lifespan by ~40% through DAF-16 and confers ER stress resistance via a non-canonical, UPR-independent pathway (PMID:27690135). EIF3L participates in stress-induced translational reprogramming, being required for ATF4 upregulation during the integrated stress response in Drosophila (PMID:41436469), and serves as a host factor co-opted by multiple viruses—it interacts with Yellow Fever Virus NS5 and PEDV M protein and is engaged by picornavirus 2Apro to facilitate eIF4G cleavage (PMID:23800076, PMID:32605758, PMID:35367208).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    Establishing that EIF3L is a bona fide subunit of the human eIF3 complex resolved the subunit composition of the largest translation initiation factor and identified its direct binding partner eIF3e (Int-6).

    Evidence Immunoprecipitation, mass spectrometry, gel filtration, and in vitro reconstitution in reticulocyte lysates with domain mapping in COS7 cells

    PMID:11590142

    Open questions at the time
    • Functional contribution of eIF3L to translation was not addressed
    • Structural basis of eIF3L–eIF3e interaction was not resolved
  2. 2012 High

    Reconstitution of the full eIF3 complex with and without eIF3L demonstrated that eIF3L is dispensable for bulk translation initiation, raising the question of what specialized role it serves.

    Evidence Cell-free co-expression of all 11 subunits, affinity purification, and in vitro translation initiation assay comparing 11-subunit and eIF3L-deficient complexes

    PMID:23063735

    Open questions at the time
    • Assay measured only bulk initiation; mRNA-selective effects were not tested
    • In vivo consequences of eIF3L loss were not examined
  3. 2016 High

    Discovery that C. elegans eif-3.L loss-of-function extends lifespan and confers ER stress resistance without impairing bulk translation revealed a regulatory role beyond canonical initiation, with lifespan extension requiring DAF-16.

    Evidence C. elegans loss-of-function genetics with lifespan assays, ER stress resistance assays, protein synthesis measurement, and epistasis with daf-16 and UPR mutants

    PMID:27690135

    Open questions at the time
    • The specific mRNA targets mediating longevity and stress phenotypes were unknown
    • Mechanism linking eIF3L to DAF-16 activation was not identified
  4. 2023 High

    Identification of eIF3k–eIF3l as an mRNA-selective regulatory module that represses RPS15A translation provided the molecular mechanism by which eIF3L controls ribosome content, proliferation, and stress resistance.

    Evidence Acute dTAG-mediated depletion with ribosome profiling, proteomics, transcriptomics, 5ʹ-UTR reporter mutagenesis, tumor growth assays, and mathematical modeling

    PMID:37155573

    Open questions at the time
    • Whether additional mRNAs besides RPS15A are directly regulated by the eIF3k–l module remains incompletely catalogued
    • Structural basis for eIF3k–l recognition of the RPS15A 5ʹ-UTR is unresolved
    • Whether this mechanism fully explains the C. elegans longevity phenotype is untested
  5. 2013 Medium

    Identification of eIF3L as a direct interaction partner of Yellow Fever Virus NS5 RdRp domain established eIF3L as a host factor co-opted during flavivirus infection.

    Evidence Yeast two-hybrid, in vitro binding, co-immunoprecipitation, and overexpression plaque assay

    PMID:23800076

    Open questions at the time
    • Functional consequence of the interaction on viral polymerase activity was not determined
    • Whether the interaction is conserved across flaviviruses was not tested
  6. 2020 Medium

    Demonstration that eIF3L interacts with PEDV M protein and that its knockdown enhances viral replication positioned eIF3L as a host restriction factor for a coronavirus.

    Evidence Co-immunoprecipitation in PEDV-infected cells, LC-MS/MS, siRNA knockdown with viral titer measurement

    PMID:32605758

    Open questions at the time
    • Mechanism by which eIF3L restricts PEDV replication is unknown
    • Relevance to other coronaviruses not examined
  7. 2022 Medium

    Picornavirus 2Apro was shown to interact with eIF3L and utilize the eIF3 complex as a platform to access and cleave eIF4G, revealing a virus strategy to hijack the eIF3 scaffold for host translation shutoff.

    Evidence Quantitative proteomics of 2Apro interacting partners and cleavage target characterization in infected cells

    PMID:35367208

    Open questions at the time
    • Direct structural evidence for 2Apro–eIF3L binding interface is lacking
    • Whether eIF3L depletion protects eIF4G from 2Apro cleavage was not tested
  8. 2022 Medium

    A CRISPR screen identified EIF3L (alongside EIF3K) as an inhibitor of plasma cell accumulation, suggesting the eIF3k–l module regulates immune cell differentiation.

    Evidence CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins with in vitro plasma cell differentiation and individual knockout validation

    PMID:35451955

    Open questions at the time
    • Target mRNAs responsible for the plasma cell phenotype are unidentified
    • In vivo immune function after eIF3L loss is untested
  9. 2025 Medium

    Placing eIF3L as a component required for stress-induced ATF4 translational upregulation in Drosophila extended its regulatory role to the integrated stress response, connecting the subunit to selective translational control under stress.

    Evidence Drosophila RNAi knockdown, TRIBE proteomics screen, ATF4 reporter assays in fat body and disease models

    PMID:41436469

    Open questions at the time
    • Whether eIF3L's role in ATF4 regulation is direct or mediated through eIF3 complex integrity is unclear
    • Mammalian validation of eIF3L requirement for ATF4 translation is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for eIF3k–l selective mRNA recognition, the full repertoire of translationally regulated mRNAs, whether the RPS15A mechanism underlies the longevity and immune phenotypes, and the functional significance of eIF3L palmitoylation.
  • No high-resolution structure of the eIF3k–l module bound to target mRNA
  • Palmitoylation sites and their functional impact are unvalidated
  • Mechanism connecting eIF3L to DAF-16 activation in C. elegans is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 3 GO:0005198 structural molecule activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 1
Partners
EIF3EEIF3KPEDV MRPS15AYFV NS5
Complex memberships
eIF3

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The human protein HSPC021 (now known as eIF3L) was identified as a subunit of the eIF3 complex through immunoprecipitation and mass spectrometry. It directly interacts with Int-6 (eIF3e), co-elutes with eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 in rabbit reticulocyte lysates and COS7 cells. A direct protein-protein interaction occurs between HSPC021 and Int-6, but a larger region of HSPC021 is required for full eIF3 incorporation compared to Int-6 binding alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat. Immunoprecipitation, mass spectrometry, gel filtration, in vitro reconstitution in reticulocyte lysates The Journal of biological chemistry High 11590142
2010 Using limited proteolysis and mass spectrometry of human eIF3, eIF3l (along with eIF3e, eIF3f, and eIF3h) was found to be exposed (not protected) when the HCV IRES RNA binds eIF3, while eIF3b is protected. This defines distinct regions of eIF3 sufficient for HCV IRES binding versus 40S ribosomal subunit binding, with eIF3 binding to the 40S subunit occurring through many redundant interactions. Limited proteolysis, mass spectrometry of eIF3–HCV IRES and eIF3–40S complexes Journal of molecular biology Medium 20816988
2012 Recombinant human eIF3 was reconstituted by co-expressing all 11 subunits in a HeLa cell-derived in vitro transcription/translation system. When eIF3l was omitted, an eIF3l-deficient complex was still assembled and purified. Both the 11-subunit complex and the eIF3l-less complex were as active as native eIF3 in a reconstituted translation initiation assay, indicating that eIF3l is a nonessential subunit for bulk translation initiation activity. Cell-free co-expression reconstitution, affinity chromatography, in vitro translation initiation assay Protein expression and purification High 23063735
2013 eIF3L was identified as a binding partner of Yellow Fever Virus NS5 RdRp domain via yeast two-hybrid screening of a human cDNA library, confirmed by in vitro binding assays and in vivo co-immunoprecipitation. The interaction maps to a conserved region in the NS5 RdRp domain. eIF3L overexpression showed a slight facilitation of YFV replication in plaque reduction assays. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, RNAi knockdown, overexpression plaque assay Virology journal Medium 23800076
2014 Biophysical characterization of recombinant full-length eIF3L expressed in E. coli showed it behaves as a monomer in solution (dynamic light scattering), adopts a predominantly α-helical structure (circular dichroism), and molecular docking predicts a strong interaction interface with eIF3k. Approximately 8 putative phosphorylation sites and one N-glycosylation site were predicted, suggesting regulation by post-translational modifications. Dynamic light scattering, circular dichroism, in silico structural modeling and molecular docking Protein and peptide letters Low 23919378
2016 Loss-of-function mutations in the C. elegans ortholog eif-3.L (eIF3l) extend lifespan by ~40% and enhance resistance to ER stress without affecting growth, development, or bulk protein synthesis rates. Lifespan extension requires the DAF-16 Forkhead transcription factor, while ER stress resistance is independent of IRE-1–XBP-1, ATF-6, PEK-1, and DAF-16, revealing a non-canonical regulatory role for eIF3l in stress responses and aging separate from its translation function. C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, genetic epistasis with daf-16 and UPR pathway mutants PLoS genetics High 27690135
2019 Androgen treatment of human prostate LNCaP cells significantly increases the palmitoylation level of eIF3L, as detected by clickable palmitate probe (Alk-C16) palmitoylome profiling coupled with quantitative mass spectrometry, identifying eIF3L as an androgen-regulated palmitoylated protein. Clickable palmitate probe (Alk-C16) metabolic labeling, quantitative mass spectrometry, palmitoylome profiling OncoTargets and therapy Medium 31239713
2019 eIF3L was found on the outer surface of colorectal cancer SW480-derived exosomes, sensitive to proteinase K proteolysis of intact exosomes, indicating it is peripherally associated with the exosome exterior and likely functions as an RNA-binding protein on the exosome surface. Proteinase K treatment of intact exosomes, Triton X-114 phase separation, label-free quantitative mass spectrometry Proteomics Medium 30865381
2020 eIF3L interacts with the PEDV membrane (M) protein as validated by co-immunoprecipitation in PEDV-infected cells. Downregulation of eIF3L expression by siRNA significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication. Co-immunoprecipitation with M-specific monoclonal antibody, LC-MS/MS identification, siRNA knockdown with viral titer readout Veterinary microbiology Medium 32605758
2022 Picornavirus 2Apro protease appears to interact with eIF3L and utilize the eIF3 complex to proteolytically access and cleave eIF4G during infection, representing a mechanism by which the virus inhibits host protein translation early in infection. Quantitative proteomics of 2Apro interacting partners, proteomic characterization of cleavage targets in infected cells The Journal of biological chemistry Medium 35367208
2022 In a CRISPR/Cas9 knockout screen of 1,213 RNA-binding proteins, EIF3L (along with EIF3K) was validated as an inhibitor of CD138+ plasma cell accumulation in vitro, and components of the CCR4-NOT complex showed the same phenotype, placing EIF3L as a regulator of plasma cell differentiation or survival. CRISPR/Cas9 knockout screen, in vitro plasma cell differentiation assay, validation of individual knockouts eLife Medium 35451955
2023 eIF3k and eIF3l form a mRNA-specific regulatory module within eIF3. Acute depletion of eIF3k (and eIF3l, which is co-downregulated with eIF3k under ER and oxidative stress) promotes global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of RPS15A mRNA translation. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA abolished these anabolic effects, and ectopic RPS15A expression mimicked eIF3k depletion. Mathematical modeling supported the model that eIF3k-l acts as a rheostat of ribosome content by controlling RPS15A synthesis. Multiomic profiling (ribosome profiling, proteomics, transcriptomics), acute subunit depletion (dTAG system), tumor growth assays, reporter assays with 5'-UTR mutations, ectopic overexpression, mathematical modeling The EMBO journal High 37155573
2025 In Drosophila, reduction of eIF3l (along with eIF3h, 40S ribosomal subunits, and other eIF3 subunits downstream of the 4EHP–NELF-E axis) suppressed ATF4 expression and its target genes, placing eIF3l as a component required for stress-induced ATF4 translational upregulation in the context of the integrated stress response. Drosophila genetics (RNAi knockdown), quantitative proteomics (TRIBE screen), ATF4 reporter assays in larval fat body and disease models Nature communications Medium 41436469

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
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
2015 Gene essentiality and synthetic lethality in haploid human cells. Science (New York, N.Y.) 657 26472760
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
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
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
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
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proceedings of the National Academy of Sciences of the United States of America 67 25805818
2011 Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network. Journal of virology 63 21994455
2017 Variable salinity responses of 12 alfalfa genotypes and comparative expression analyses of salt-response genes. Scientific reports 44 28225027
2019 Surfaceome of Exosomes Secreted from the Colorectal Cancer Cell Line SW480: Peripheral and Integral Membrane Proteins Analyzed by Proteolysis and TX114. Proteomics 43 30865381
2016 Mutations in Nonessential eIF3k and eIF3l Genes Confer Lifespan Extension and Enhanced Resistance to ER Stress in Caenorhabditis elegans. PLoS genetics 43 27690135
2018 Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population. Biomedical reports 31 30402224
2010 Distinct regions of human eIF3 are sufficient for binding to the HCV IRES and the 40S ribosomal subunit. Journal of molecular biology 30 20816988
2001 The human protein HSPC021 interacts with Int-6 and is associated with eukaryotic translation initiation factor 3. The Journal of biological chemistry 26 11590142
2013 The eukaryotic translation initiation factor 3 subunit L protein interacts with Flavivirus NS5 and may modulate yellow fever virus replication. Virology journal 23 23800076
2020 Identification of host cell proteins that interact with the M protein of porcine epidemic diarrhea virus. Veterinary microbiology 22 32605758
2015 Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts. Cell cycle (Georgetown, Tex.) 22 25785348
2023 eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content. The EMBO journal 20 37155573
2021 eIF3k Domain-Containing Protein Regulates Conidiogenesis, Appressorium Turgor, Virulence, Stress Tolerance, and Physiological and Pathogenic Development of Magnaporthe oryzae Oryzae. Frontiers in plant science 18 34733303
2022 A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells. eLife 17 35451955
2019 An integrative genomic analysis of transcriptional profiles identifies characteristic genes and patterns in HIV-infected long-term non-progressors and elite controllers. Journal of translational medicine 15 30665429
2019 Androgen upregulates the palmitoylation of eIF3L in human prostate LNCaP cells. OncoTargets and therapy 12 31239713
2016 The Rice Eukaryotic Translation Initiation Factor 3 Subunit f (OseIF3f) Is Involved in Microgametogenesis. Frontiers in plant science 12 27200010
2022 Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease. The Journal of biological chemistry 11 35367208
2012 Reconstitution of eukaryotic translation initiation factor 3 by co-expression of the subunits in a human cell-derived in vitro protein synthesis system. Protein expression and purification 9 23063735
2022 Global landscape of protein complexes in postprandial-state livers from diet-induced obese and lean mice. Biochemical and biophysical research communications 8 36099783
2022 Loop-mediated isothermal amplification (LAMP) assays for detection of the New Guinea fruit fly Bactrocera trivialis (Drew) (Diptera: Tephritidae). Scientific reports 7 35871253
2022 Poor maternal diet during gestation alters offspring muscle proteome in sheep. Journal of animal science 6 35908790
2023 Evaluation of identification methods for cryptic Bactrocera dorsalis (Diptera: Tephritidae) specimens: combining morphological and molecular techniques. Journal of economic entomology 4 37824174
2014 Biophysical and structural characterization of the recombinant human eIF3L. Protein and peptide letters 4 23919378
2009 Ethanolic Hwaeumjeon induces mitochondrial dependent apoptosis partly via PI3K/AKT/HSP27/ERK pathways and inhibits PSA and AR in LNCaP cells. Environmental toxicology and pharmacology 4 21783985
2024 QTL-seq identifies genomic region associated with the crown root development under Jasmonic acid response. Functional & integrative genomics 2 39160350
2008 Hepatocellular carcinoma-related gene targeting using the large circular antisense library. Oncology reports 2 18813834
2025 Estimation of genome-wide patterns of homozygosity, heterozygosity and inbreeding in crossbred dairy cattle population in Pakistan. Tropical animal health and production 1 41003855
2026 Domain architecture of plant eukaryotic translation initiation factor 3 subunit E governs interaction with translational cis-elements to regulatepollen tube growth. The Plant cell 0 41701515
2025 Multi-Omics and Clinical Validation Identify Key Glycolysis- and Immune-Related Genes in Sepsis. International journal of general medicine 0 40927774
2025 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila. Nature communications 0 41436469