EIF3F

EIF3F is a subunit of the eIF3 translation initiation complex that couples nutrient/growth signaling to protein synthesis and, through an independent intrinsic deubiquitinase activity, controls the stability of multiple metabolic and oncogenic substrates (PMID:41423661, PMID:21124883, PMID:37544925). In skeletal muscle, eIF3f carries a TOS motif that bridges the mTOR/raptor complex to enable S6K1 and rpS6 phosphorylation, thereby driving translation and hypertrophy (PMID:20126553); this output is negatively gated by the E3 ligase MAFbx/Atrogin-1, which polyubiquitinates eIF3f at six C-terminal lysines and targets it for proteasomal degradation during atrophy, while a degradation-resistant mutant sustains S6K1 signaling and protects against atrophy (PMID:18354498, PMID:19073596, PMID:20126553). eIF3f is required for normal development and muscle mass: homozygous knockout is embryonic lethal and heterozygous loss reduces muscle protein synthesis, polysome content, and mTOR activity (PMID:31026345). Beyond canonical initiation, eIF3f acts as a deubiquitinase that removes monoubiquitin from activated Notch1 to license gamma-secretase processing (PMID:21124883), and stabilizes the metabolic enzymes PHGDH, ACSL4, and FASN — the latter two via K48-linked chain removal — while also deubiquitinating MYC, linking it to serine/one-carbon and lipid metabolism in colorectal, hepatocellular, and prostate cancers (PMID:37544925, PMID:40154622, PMID:42231807). eIF3f additionally tunes specialized RNA processes, restricting HIV-1 pre-mRNA 3' end processing in a complex with 9G8 and CDK11 (PMID:19854136, PMID:19237569), promoting stress-induced rRNA degradation by dissociating hnRNP K from rRNA (PMID:22457825), and regulating IRES-mediated translation of Bcl-xL through interaction with PDCD4 (PMID:42123540). Proximity labeling places eIF3f with eIF3/eIF4E/eIF4G/eIF5 initiation machinery and assigns it nuclear, Z-disc (SYNPO2), and lysosomal (LAMP1) localizations in muscle cells (PMID:41423661).

1. 2008 High

   Established how eIF3f abundance is controlled during muscle wasting, identifying it as the degradation target that links an atrophy E3 ligase to loss of translational capacity.

   Evidence Co-IP, MAFbx shRNA knockdown and overexpression in myotubes plus in vivo mouse muscle

   PMID:18354498

   Open questions at the time

   • Did not define the lysines required for ubiquitination
   • Did not establish the downstream signaling effector of eIF3f
2. 2008 High

   Mapped the molecular determinant of eIF3f turnover, showing six C-terminal lysines are the ubiquitin acceptor sites whose mutation confers atrophy resistance.

   Evidence Site-directed mutagenesis (K5-10R), deletion analysis, in cellulo and in vivo overexpression

   PMID:19073596

   Open questions at the time

   • Did not yet connect resistance to a specific signaling pathway
3. 2010 High

   Defined the mechanism by which eIF3f drives hypertrophy, showing a TOS motif scaffolds mTOR/raptor to enable S6K1 activation.

   Evidence TOS motif mutagenesis, immunoprecipitation, phosphorylation assays in myotubes

   PMID:20126553

   Open questions at the time

   • Did not resolve stoichiometry of the eIF3f-raptor-S6K1 interaction
   • Did not test requirement in vivo at this stage
4. 2010 High

   Revealed an entirely separate enzymatic role, demonstrating eIF3f is an intrinsic deubiquitinase acting on monoubiquitinated Notch1 to permit gamma-secretase processing.

   Evidence shRNA screen, catalytically inactive mutant rescue, Notch coculture activation assay, Deltex1 bridging

   PMID:21124883

   Open questions at the time

   • Did not identify the catalytic residues or structural basis of DUB activity
   • Did not survey the full substrate range
5. 2008 Medium

   Showed eIF3f can be hijacked by coronavirus spike proteins to suppress host translation, the first link to viral pathogenesis.

   Evidence Yeast two-hybrid, Co-IP, immunofluorescence, translation reporter assays

   PMID:18231581

   Open questions at the time

   • Mechanism of translational suppression by the S-protein interaction not resolved
   • Single lab
6. 2009 High

   Identified an antiviral RNA-processing role, showing eIF3f blocks HIV-1 pre-mRNA 3' end processing within a 9G8/CDK11 complex.

   Evidence cDNA library screen, in vivo and in vitro 3' end processing assays, cofactor identification across two papers

   PMID:19237569 PMID:19854136

   Open questions at the time

   • Whether this processing role generalizes to host mRNAs unclear
   • Catalytic vs scaffolding contribution not separated
7. 2012 Medium

   Connected eIF3f to rRNA homeostasis under stress, showing it dissociates hnRNP K from rRNA to permit degradation in distinct cytoplasmic foci.

   Evidence Stable knockdown, Co-IP, translation and rRNA stability assays, subcellular imaging

   PMID:22457825

   Open questions at the time

   • Nuclease responsible for rRNA degradation not identified
   • Relationship of foci to canonical RNA granules unresolved
8. 2013 Medium

   Linked eIF3f to the DNA damage response through hMSH4 binding that modulates NHEJ repair and AKT activation after irradiation.

   Evidence Co-IP, deletion mapping, knockdown, cell survival and DNA damage assays

   PMID:23725059

   Open questions at the time

   • Direct role of eIF3f at DSB sites not shown
   • Single lab, mechanism of NHEJ down-regulation indirect
9. 2015 Medium

   Extended eIF3f's interactome to secretory clusterin and the alpha-1B-adrenergic receptor, implicating it in tumor suppression and adrenoceptor signaling.

   Evidence Co-IP with domain mapping, xenograft model; native Co-IP and adrenoceptor activity assay

   PMID:26497985 PMID:26988917

   Open questions at the time

   • Adrenoceptor interaction rests on single low-confidence Co-IP without reciprocal validation
   • Mechanism of sCLU modification blockade not defined
10. 2018 Medium

    Implicated eIF3f in non-canonical RAN translation, broadening its translational regulatory scope to repeat-expansion disease pathology.

    Evidence siRNA knockdown with RAN protein readouts for multiple repeat expansions

    PMID:30206144

    Open questions at the time

    • Direct binding to repeat RNAs not demonstrated
    • Single lab
11. 2018 Medium

    Embedded eIF3f in estrogen-receptor signaling, showing dual transcriptional repression and mTORC1-driven translational control of its own expression in breast cancer.

    Evidence ERalpha knockdown/overexpression, mTORC1 inhibition, polysome profiling, reporter assays

    PMID:30573685

    Open questions at the time

    • Causal link between eIF3f level and proliferation correlative
    • Single lab
12. 2019 High

    Provided definitive in vivo genetic proof that eIF3f is essential for development and for sustaining muscle protein synthesis through the mTOR pathway.

    Evidence Knockout mouse model, polysome profiling, synthesis rate, hindlimb immobilization atrophy model

    PMID:31026345

    Open questions at the time

    • Cause of embryonic lethality not dissected
    • Tissue-specific contributions beyond muscle untested
13. 2023 Medium

    Established eIF3f as a metabolic regulator in cancer, using DUB activity to stabilize PHGDH and MYC and amplify the serine/one-carbon pathway downstream of Wnt and EGF.

    Evidence Co-IP, ubiquitination and DUB assays, pathway inhibition in colorectal cancer

    PMID:37544925

    Open questions at the time

    • Direct vs indirect MYC deubiquitination not fully separated
    • Single lab
14. 2025 Medium

    Showed eIF3f drives lipid biosynthesis by K48-linked deubiquitination and stabilization of ACSL4, with phosphorylation enhancing the interaction in liver cancer.

    Evidence Co-IP, ubiquitination assays, metabolomics, metabolic flux, organoid and in vivo models

    PMID:40154622

    Open questions at the time

    • Kinase phosphorylating eIF3f not identified
    • Single lab
15. 2025 Medium

    Defined the endogenous eIF3f interactome and unexpected localizations, placing it with initiation machinery and at nuclear, Z-disc, and lysosomal compartments in muscle.

    Evidence CRISPR endogenous BioID, streptavidin pulldown, mass spectrometry, immunofluorescence

    PMID:41423661

    Open questions at the time

    • Functional significance of nuclear and lysosomal pools not established
    • Proximity does not prove direct binding
16. 2026 Medium

    Connected eIF3f to selective IRES-driven survival translation via RNA-independent interaction with PDCD4 and binding to the Bcl-xL IRES.

    Evidence Co-IP, IRES reporter, polysome profiling, EMSA, knockdown

    PMID:42123540

    Open questions at the time

    • Whether eIF3f acts catalytically or as adaptor on the IRES unresolved
    • Single lab
17. 2026 Medium

    Identified a chaperonin-assisted mechanism in which CCT2 forms a ternary complex enabling eIF3f-mediated deubiquitination and stabilization of FASN in prostate cancer.

    Evidence Co-IP, ubiquitination assays, isograft/PDX models, small-molecule interaction inhibitor

    PMID:42231807

    Open questions at the time

    • Role of CCT2 chaperone function vs scaffolding not separated
    • Single lab

• How the same protein partitions between its eIF3 initiation role and its deubiquitinase activity — and what governs substrate selection, catalytic residues, and compartment-specific functions — remains unresolved.
• No structural model of the eIF3f DUB active site or its substrate-recognition determinants
• Mechanism switching initiation vs DUB roles undefined
• Function of nuclear and lysosomal eIF3f pools uncharacterized