Affinage

EIF3L

Eukaryotic translation initiation factor 3 subunit L · UniProt Q9Y262

Length
564 aa
Mass
66.7 kDa
Annotated
2026-06-09
31 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF3L is an accessory subunit of the human eIF3 translation initiation complex that integrates into eIF3 through a direct interaction with the eIF3E (Int-6) subunit, an association mediated by the PCI domain and dependent on phosphorylation (PMID:11590142, PMID:41701515). A larger region of EIF3L is needed for incorporation into the assembled complex than for eIF3E binding alone, and the protein carries TPR, PCI, and Pumilio FBF repeats (PMID:11590142). EIF3L is dispensable for both bulk eIF3 assembly and general translation initiation: an eIF3l-deficient complex reconstituted in vitro remains fully active (PMID:23063735). Its principal regulatory role is as part of an eIF3k–eIF3l module that selectively represses translation of specific mRNAs, notably RPS15A, by binding the RPS15A 5'-UTR; loss of either subunit relieves this repression to drive global translation, proliferation, tumor growth, and stress resistance, and these subunits are selectively downregulated under ER and oxidative stress (PMID:37155573). Consistent with this anti-anabolic, pro-survival rheostat function, loss of the C. elegans ortholog extends lifespan in a DAF-16–dependent manner and confers ER-stress resistance without altering bulk protein synthesis (PMID:27690135). EIF3L is regulated by post-translational modifications including H2O2-induced tyrosine phosphorylation (PMID:11590142) and androgen-induced palmitoylation (PMID:31239713). Beyond its endogenous role, EIF3L is co-opted by multiple RNA viruses: it interacts directly with the flavivirus NS5 RdRp domain (PMID:23800076) and the PEDV M protein (PMID:32605758), is required for influenza polymerase activity (PMID:21994455), and serves as a scaffold through which picornavirus 2Apro reaches and cleaves eIF4G (PMID:35367208).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Established EIF3L as a bona fide eIF3-associated protein, answering whether this uncharacterized protein physically joins the translation initiation machinery and through which subunit.

    Evidence Reciprocal Co-IP, gel filtration co-elution, and deletion mapping in reticulocyte lysate and COS7 cells identifying direct binding to Int-6/eIF3E

    PMID:11590142

    Open questions at the time
    • Did not define the functional consequence of EIF3L within eIF3
    • Role of the TPR/PCI/Pumilio repeats not functionally dissected
    • Significance of H2O2-induced tyrosine phosphorylation left open
  2. 2010 Medium

    Mapped EIF3L's spatial relationship within eIF3 bound to an IRES and the 40S subunit, distinguishing exposed accessory subunits from those protected upon RNA engagement.

    Evidence Limited proteolysis with mass spectrometry of human eIF3–HCV IRES–40S complexes

    PMID:20816988

    Open questions at the time
    • Topology inferred indirectly from proteolytic accessibility
    • Functional role of EIF3L in IRES-driven initiation not tested
  3. 2011 Medium

    Showed EIF3L is required for influenza polymerase activity, opening its role as a virus-utilized host factor.

    Evidence Yeast two-hybrid screen for polymerase interactors plus RNAi knockdown with viral polymerase transcription readout

    PMID:21994455

    Open questions at the time
    • Direct binding to polymerase not biochemically confirmed
    • Whether the effect reflects eIF3 function or a distinct activity unclear
  4. 2012 High

    Demonstrated that EIF3L is a nonessential subunit, resolving whether it is required for eIF3 assembly and core initiation activity.

    Evidence Cell-free co-expression reconstitution of human eIF3 with and without eIF3l plus a reconstituted translation initiation activity assay

    PMID:23063735

    Open questions at the time
    • Did not address selective/mRNA-specific roles missed by a bulk activity assay
    • Stress-dependent functions not examined
  5. 2013 Medium

    Identified direct EIF3L–flavivirus NS5 interaction, broadening the catalogue of viral proteins that engage EIF3L.

    Evidence Yeast two-hybrid, in vitro binding, Co-IP, NS5 domain mutagenesis, and overexpression/RNAi plaque assays for Yellow Fever Virus

    PMID:23800076

    Open questions at the time
    • Functional effect on replication only slight
    • Mechanism by which NS5 binding aids replication unresolved
    • Single lab
  6. 2014 Low

    Provided biophysical characterization of recombinant EIF3L and computationally predicted an eIF3K partnership.

    Evidence Dynamic light scattering, circular dichroism, and in silico docking of recombinant human eIF3L

    PMID:23919378

    Open questions at the time
    • eIF3K interaction is computational, not experimentally validated here
    • Predicted phosphorylation and glycosylation sites not confirmed
  7. 2015 Medium

    Linked EIF3L to oncogenic phenotypes and stress states via post-translational modification, raising regulatory complexity beyond constitutive eIF3 membership.

    Evidence SUMO proteomics with anchorage-independent growth RNAi in KRAS-mutant cells; ubiquitinated-peptide LC-MS/MS in oncogene-induced senescent fibroblasts

    PMID:25785348 PMID:25805818

    Open questions at the time
    • EIF3L's individual contribution to growth not separated from KAP1/CHD1
    • SUMO and ubiquitin sites lack writer/eraser and functional follow-up
  8. 2016 High

    Established an organismal phenotype for EIF3L loss, showing it normally limits longevity and stress resistance independent of bulk translation.

    Evidence C. elegans loss-of-function genetics with lifespan/ER-stress assays and epistasis against daf-16, ire-1, atf-6, pek-1

    PMID:27690135

    Open questions at the time
    • Molecular target through which eif-3.L loss extends lifespan not identified
    • DAF-16-dependence of lifespan vs DAF-16-independence of ER-stress resistance left mechanistically unexplained
  9. 2019 Medium

    Identified androgen-induced palmitoylation as a hormone-responsive modification of EIF3L.

    Evidence Clickable-palmitate palmitoylome profiling with MS in androgen-treated LNCaP cells

    PMID:31239713

    Open questions at the time
    • Palmitoylation site and enzyme not identified
    • Functional consequence for EIF3L activity unknown
  10. 2022 Medium

    Defined two distinct roles: EIF3L as a scaffold exploited by picornavirus 2Apro to cleave eIF4G, and as a regulator of plasma cell differentiation.

    Evidence Proteomic mapping of 2Apro partners with cleavage assays; CRISPR/Cas9 knockout with flow cytometry in an in vitro B cell differentiation system

    PMID:35367208 PMID:35451955

    Open questions at the time
    • 2Apro–eIF3L scaffolding model not reconstituted
    • Mechanism linking EIF3L to CD138+ plasma cell suppression unresolved
  11. 2023 High

    Defined EIF3L's core endogenous mechanism as a selective translational repressor acting with eIF3k to suppress RPS15A and tune ribosome content and stress resistance.

    Evidence Ribosome profiling, proteomics, transcriptomics on acute eIF3 subunit depletion with RPS15A rescue, 5'-UTR reporter mutagenesis, and in vivo tumor assays

    PMID:37155573

    Open questions at the time
    • How EIF3L confers mRNA selectivity at the molecular level not fully resolved
    • Signal coupling stress to eIF3k/eIF3l downregulation not defined
  12. 2020 Medium

    Showed EIF3L acts as a negative regulator of PEDV replication through interaction with the viral M protein.

    Evidence Co-IP with LC-MS/MS plus RNAi knockdown with viral titer measurement

    PMID:32605758

    Open questions at the time
    • Mechanism of replication restriction unknown
    • Direct binding interface not mapped
  13. 2025 Medium

    Placed EIF3L within an ATF4 regulatory network alongside 4EHP and NELF-E, connecting it to stress-responsive gene induction.

    Evidence Drosophila knockdown genetics, quantitative proteomics, and ATF4 reporter assays

    PMID:41436469

    Open questions at the time
    • Whether EIF3L acts directly on ATF4 mRNA translation unclear
    • One of several factors tested; specificity not isolated
  14. 2026 Medium

    Confirmed the eIF3E PCI-domain, phosphorylation-dependent basis of the eIF3E–eIF3L interaction and its requirement for selective mRNA translation in a conserved system.

    Evidence AlphaFold3 modeling, FRET, PCI-domain deletion and phosphosite mutagenesis, and mRNA reporter assays in plant eIF3

    PMID:41701515

    Open questions at the time
    • Demonstrated in plants, not human; transferability assumed
    • Kinase controlling the PCI phosphosites not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EIF3L confers transcript selectivity, what signals trigger its stress-induced downregulation, and the functional consequences of its multiple post-translational modifications remain unresolved.
  • No structural model of human EIF3L within the selective repression module
  • Enzymes writing/erasing palmitoylation, SUMOylation, ubiquitination, and tyrosine phosphorylation unidentified
  • Whether viral host-factor roles are separable from the endogenous eIF3k–eIF3l module is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 2 GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
EIF3EEIF3K
Complex memberships
eIF3

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HSPC021 (EIF3L) was identified as a protein associated with eIF3 subunit Int-6 (EIF3E). Direct protein-protein interaction occurs between HSPC021 and Int-6. HSPC021 coelutes with Int-6 and eIF3 in gel filtration, coimmunoprecipitates with eIF3, and is incorporated into eIF3 both in rabbit reticulocyte lysates and in COS7 cells. A larger region of HSPC021 is required for incorporation into eIF3 than for binding to Int-6 alone. The protein contains a tetratricopeptide repeat, a PCI domain, and a Pumilio FBF repeat. Exposure to H2O2 triggers tyrosine phosphorylation of HSPC021. Immunoprecipitation, mass spectrometry, gel filtration, cell-based coimmunoprecipitation (rabbit reticulocyte lysates and COS7 cells), deletion mutant analysis The Journal of biological chemistry High 11590142
2010 eIF3l (along with other eIF3 subunits) is exposed (not protected) when eIF3 binds the HCV IRES RNA, whereas eIF3b is protected by HCV IRES RNA binding. Limited proteolysis revealed that eIF3l is among the subunits exposed upon HCV IRES binding but is involved in broader redundant interactions with the 40S ribosomal subunit. Limited proteolysis combined with mass spectrometry of human eIF3 in complex with HCV IRES RNA and 40S ribosomal subunit Journal of molecular biology Medium 20816988
2012 eIF3l is a nonessential subunit of the eIF3 complex: when eIF3l was omitted from a cell-free reconstitution of the 11-subunit human eIF3 complex, an eIF3l-deficient complex was still assembled and was as active as the native 11-subunit complex in a reconstituted translation initiation assay. Cell-free co-expression reconstitution in HeLa-derived in vitro transcription/translation system, affinity chromatography purification, reconstituted translation initiation activity assay Protein expression and purification High 23063735
2013 eIF3L interacts directly with Yellow Fever Virus (YFV) NS5 protein (RdRp domain). The interaction was confirmed by yeast two-hybrid, in vitro binding assay, and in vivo coimmunoprecipitation. The interaction domain on NS5 is conserved across several flaviviruses. eIF3L overexpression showed a slight facilitating effect on YFV replication in plaque assays. Yeast two-hybrid screen, in vitro binding assay, coimmunoprecipitation, site-directed mutagenesis of NS5 interaction domain, eIF3L overexpression and RNAi knockdown with plaque reduction assay Virology journal Medium 23800076
2014 Recombinant full-length human eIF3L produced in E. coli behaves as a monomer when not interacting with other molecular partners (by dynamic light scattering). Circular dichroism revealed predominantly α-helical secondary structure. In silico molecular docking predicted strong interaction between eIF3L and eIF3K. Multiple putative phosphorylation sites (~8) and one N-glycosylation site were predicted bioinformatically. Dynamic light scattering, circular dichroism spectroscopy, in silico structural modeling and molecular docking Protein and peptide letters Low 23919378
2016 Loss-of-function mutations in eif-3.L (the C. elegans ortholog of EIF3L) result in ~40% lifespan extension and enhanced resistance to ER stress, without affecting bulk protein synthesis rates or growth. Lifespan extension from EIF-3.L deficiency is suppressed by a mutation in the DAF-16 Forkhead transcription factor. ER stress resistance conferred by eif-3.L loss is independent of IRE-1/XBP-1, ATF-6, PEK-1, and DAF-16 signaling. C. elegans loss-of-function genetics, lifespan assays, ER stress resistance assays, bulk protein synthesis measurement, epistasis analysis with daf-16, ire-1, atf-6, pek-1 mutants PLoS genetics High 27690135
2011 EIF3S6IP (EIF3L) was identified as a host factor required for influenza virus polymerase replication and transcriptional activity. RNAi-mediated depletion of EIF3L reduced viral polymerase transcriptional activity in a functional screen. Yeast two-hybrid screen for influenza polymerase interactors, RNAi knockdown with viral polymerase transcriptional activity assay Journal of virology Medium 21994455
2020 eIF3L interacts with PEDV (porcine epidemic diarrhea virus) membrane (M) protein, validated by coimmunoprecipitation. Downregulation of eIF3L expression significantly increased PEDV viral production, indicating eIF3L acts as a negative regulator of PEDV replication. Co-immunoprecipitation with LC-MS/MS, RNAi knockdown with viral titer measurement Veterinary microbiology Medium 32605758
2022 eIF3L is utilized by picornavirus 2Apro to gain proteolytic access to eIF4G: the protease appears to interact with eIF3L, using the eIF3 complex as a scaffold to reach and cleave eIF4G, rather than directly binding eIF4G. This was established through proteomic characterization of 2Apro interacting partners. Proteomic analysis of 2Apro interacting partners, cleavage assays, proteomic identification of cleavage targets The Journal of biological chemistry Medium 35367208
2022 EIF3K and EIF3L subunits function as inhibitors of CD138+ plasma cell accumulation in vitro. CRISPR/Cas9 knockout of EIF3L in mouse B cells promoted accumulation of CD138+ plasma cells, validated in an in vitro differentiation system. CRISPR/Cas9 knockout screen of 1213 RNA binding proteins, flow cytometry for CD138+ cell abundance, in vitro B cell differentiation eLife Medium 35451955
2023 eIF3k and eIF3l form a mRNA-specific regulatory module within the eIF3 complex. Depletion of eIF3k or eIF3l promoted global translation, cell proliferation, tumor growth, and stress resistance by relieving repression of ribosomal protein RPS15A synthesis. eIF3k and eIF3l are selectively downregulated in response to ER stress and oxidative stress. Disruption of eIF3 binding to the 5'-UTR of RPS15A mRNA negated the anabolic effects of eIF3k depletion. eIF3l depletion phenocopied eIF3k depletion in this context. Multiomic profiling (ribosome profiling, proteomics, transcriptomics) upon acute eIF3 subunit depletion, tumor growth assays, RPS15A ectopic expression rescue, 5'-UTR reporter mutagenesis, mathematical modeling The EMBO journal High 37155573
2019 Androgen treatment significantly increases the palmitoylation level of eIF3L in human prostate LNCaP cells, as identified by palmitoylome profiling using a clickable palmitate probe. Palmitoylome profiling using clickable palmitate probe (Alk-C16) with mass spectrometry in androgen-treated vs. untreated LNCaP cells OncoTargets and therapy Medium 31239713
2015 EIF3L is among the proteins with elevated SUMOylation in KRAS mutant colorectal cancer cells. EIF3L (along with KAP1 and CHD1) collectively supports anchorage-independent growth in KRAS mutant cells. Quantitative proteomics of SUMOylated proteins in KRAS mutant cells, RNAi knockdown of EIF3L with anchorage-independent 3D growth assay Proceedings of the National Academy of Sciences of the United States of America Medium 25805818
2015 eIF3L is ubiquitinated during oncogene-induced senescence (OIS) in primary human fibroblasts, as part of a broader pattern of ubiquitination affecting translation machinery components. Ubiquitinated peptide enrichment by immune affinity purification followed by LC-MS/MS in RAS-induced OIS cells Cell cycle (Georgetown, Tex.) Low 25785348
2025 In Drosophila, reduction of eIF3l (along with 4EHP, NELF-E, RpS12, and eIF3h) suppressed ATF4 expression and ATF4 target gene induction, placing eIF3l as a component of an ATF4 regulatory network that also includes 4EHP and NELF-E. Quantitative proteomics showed that knockdown of NELF-E or 4EHP reduced levels of eIF3 subunits including eIF3l. Drosophila genetics (knockdown), quantitative proteomics, ATF4 reporter assays Nature communications Medium 41436469
2026 In plant eIF3, the PCI domain of eIF3E is required for eIF3E–eIF3L interaction: deletion of the PCI domain or mutation of PCI phosphosites (Thr417, Ser421) weakened eIF3E–eIF3L interaction (by FRET) and blocked translational activation of an mRNA reporter bearing a coding-sequence motif (MC2). This establishes eIF3L as a binding partner of eIF3E whose interaction is phosphorylation-dependent and functionally required for selective mRNA translation. Affinity RNA immunoprecipitation sequencing, AlphaFold3 structural modeling, FRET (Förster resonance energy transfer), mRNA reporter assay, domain deletion and phosphosite mutagenesis The Plant cell Medium 41701515

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 68 25805818
2011 Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network. Journal of virology 63 21994455
2019 Surfaceome of Exosomes Secreted from the Colorectal Cancer Cell Line SW480: Peripheral and Integral Membrane Proteins Analyzed by Proteolysis and TX114. Proteomics 45 30865381
2017 Variable salinity responses of 12 alfalfa genotypes and comparative expression analyses of salt-response genes. Scientific reports 44 28225027
2016 Mutations in Nonessential eIF3k and eIF3l Genes Confer Lifespan Extension and Enhanced Resistance to ER Stress in Caenorhabditis elegans. PLoS genetics 44 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 16 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
2022 Loop-mediated isothermal amplification (LAMP) assays for detection of the New Guinea fruit fly Bactrocera trivialis (Drew) (Diptera: Tephritidae). Scientific reports 9 35871253
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 Poor maternal diet during gestation alters offspring muscle proteome in sheep. Journal of animal science 7 35908790
2023 Evaluation of identification methods for cryptic Bactrocera dorsalis (Diptera: Tephritidae) specimens: combining morphological and molecular techniques. Journal of economic entomology 5 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
2008 Hepatocellular carcinoma-related gene targeting using the large circular antisense library. Oncology reports 3 18813834
2024 QTL-seq identifies genomic region associated with the crown root development under Jasmonic acid response. Functional & integrative genomics 2 39160350
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
2025 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila. Nature communications 1 41436469
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

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