EIF3F

EIF3F is a subunit of the eIF3 translation initiation complex that functions both as a scaffold for mTORC1-S6K1 signaling to regulate protein synthesis and as an intrinsic deubiquitinase (DUB) with broad substrate specificity. Through a conserved TOS motif, eIF3f bridges the mTOR/raptor complex to S6K1, enabling mTOR-dependent phosphorylation that promotes translation and skeletal muscle hypertrophy; the E3 ligase MAFbx/Atrogin-1 polyubiquitinates six C-terminal lysines of eIF3f to target it for proteasomal degradation during muscle atrophy, and homozygous knockout in mice is embryonic lethal while heterozygotes exhibit reduced muscle mass and protein synthesis (PMID:18354498, PMID:19073596, PMID:20126553, PMID:31026345). The DUB activity of eIF3f deubiquitinates monoubiquitinated Notch1 on endocytic vesicles to enable γ-secretase cleavage and Notch activation, stabilizes PHGDH and MYC to enhance serine-glycine-one-carbon metabolism in colorectal cancer, and removes K48-linked ubiquitin from ACSL4 to promote fatty acid biosynthesis in hepatocellular carcinoma (PMID:21124883, PMID:37544925, PMID:40154622). Independent of its translation and DUB roles, eIF3f forms a complex with the SR protein 9G8 and CDK11 to inhibit HIV-1 pre-mRNA 3′-end processing, revealing a non-canonical function in RNA metabolism (PMID:19854136).

1. 2008 High

   Establishing how eIF3f is degraded during muscle atrophy resolved why translation capacity declines in wasting conditions: the E3 ligase MAFbx/Atrogin-1 polyubiquitinates eIF3f for proteasomal destruction, and six C-terminal lysines are the critical ubiquitination sites.

   Evidence Co-IP, shRNA knockdown, ectopic expression in myotubes and in vivo mouse muscle; site-directed mutagenesis with in vitro ubiquitination assay

   PMID:18354498 PMID:19073596

   Open questions at the time

   • Which individual lysines are preferentially ubiquitinated in vivo is not resolved
   • Whether other E3 ligases target eIF3f in non-muscle tissues is unknown
2. 2008 Medium

   Interaction of eIF3f with coronavirus spike proteins and inhibition of cap-dependent translation provided early evidence that eIF3f can be co-opted by viral proteins to modulate host translation.

   Evidence Yeast two-hybrid, Co-IP, in vitro translation and reporter assays with SARS-CoV and IBV spike proteins

   PMID:18231581

   Open questions at the time

   • Whether eIF3f–spike interaction occurs during natural infection and its physiological relevance remain untested
   • Structural basis for the interaction is unknown
3. 2009 High

   Discovery that eIF3f inhibits HIV-1 replication by blocking pre-mRNA 3′-end processing — through a complex with 9G8 and CDK11 — revealed a non-canonical, translation-independent function in RNA metabolism.

   Evidence cDNA expression screen, in vitro and in vivo 3′ processing assays, Co-IP for eIF3f–9G8–CDK11 complex

   PMID:19237569 PMID:19854136

   Open questions at the time

   • Whether this RNA processing role extends to cellular pre-mRNAs beyond HIV-1 is unknown
   • The catalytic or structural basis by which eIF3f modulates 9G8 specificity is not defined
4. 2010 High

   Identification of a TOS motif in eIF3f that recruits mTORC1/raptor to activate S6K1 established eIF3f as a scaffold linking translation initiation to mTOR signaling, explaining why MAFbx-mediated eIF3f loss suppresses anabolic signaling.

   Evidence Co-IP of eIF3f with mTOR/raptor, TOS motif mutagenesis, S6K1/rpS6 phosphorylation assays

   PMID:20126553

   Open questions at the time

   • Whether the TOS motif functions within the assembled eIF3 complex or only on free eIF3f is unclear
   • Direct structural evidence for the eIF3f–raptor interface is lacking
5. 2010 High

   Demonstration that eIF3f possesses intrinsic deubiquitinase activity — deubiquitinating monoubiquitinated Notch1 on endosomes via Deltex1 recruitment — established a second enzymatic identity for this translation factor outside translation.

   Evidence shRNA screen, catalytically inactive mutant rescue, coculture Notch activation assay, Co-IP

   PMID:21124883

   Open questions at the time

   • The catalytic mechanism and active-site residues have not been structurally characterized
   • Whether Deltex1-independent DUB substrates use the same recruitment mechanism is unknown
6. 2012 Medium

   Discovery that eIF3f promotes rRNA degradation by displacing hnRNP K under stress, and that eIF3f loss causes cytokinesis defects and apoptotic resistance, broadened eIF3f's role to ribosome quality control and cell division.

   Evidence Co-IP of eIF3f–hnRNP K, rRNA stability assays, shRNA knockdown with proliferation and apoptosis readouts in pancreatic cells

   PMID:22457825

   Open questions at the time

   • The mechanism linking eIF3f to cytokinesis is not defined
   • Whether rRNA degradation requires eIF3f's DUB activity or is a distinct function is untested
7. 2018 Medium

   Estrogen receptor α was shown to dually regulate eIF3f — repressing transcription while boosting mRNA translation via mTORC1 — and eIF3f levels selectively control translation of structured 5′-UTR mRNAs (cyclin D1, survivin), linking eIF3f to selective mRNA translation.

   Evidence ChIP, reporter assays, polysome profiling, mTORC1 inhibition

   PMID:30573685

   Open questions at the time

   • The full repertoire of eIF3f-dependent translationally regulated mRNAs is not defined
   • Whether eIF3f contacts structured 5′-UTRs directly or through other eIF3 subunits is unknown
8. 2019 High

   Genetic knockout in mice confirmed eIF3f is essential for embryonic development and that haploinsufficiency reduces muscle mass, polysome content, and mTOR signaling, validating the cell-based atrophy/hypertrophy model in a whole-organism context.

   Evidence Homozygous and heterozygous eIF3f knockout mice, polysome profiling, protein synthesis measurements, hindlimb immobilization

   PMID:31026345

   Open questions at the time

   • The embryonic lethal stage and cause of death in homozygous knockouts are not characterized
   • Tissue-specific conditional knockouts have not been reported
9. 2023 Medium

   eIF3f's DUB activity was extended to cancer metabolism: it stabilizes PHGDH by counteracting FBXW7β-mediated ubiquitination and deubiquitinates MYC to enhance SGOC pathway activity in colorectal cancer, connecting Wnt-driven EIF3F expression to metabolic reprogramming.

   Evidence Co-IP, ubiquitination assays, metabolomics, shRNA knockdown and rescue in colorectal cancer cells

   PMID:37544925

   Open questions at the time

   • Whether eIF3f's DUB and translation functions are separable in cancer cells has not been tested with catalytic mutants
   • In vivo tumor models with DUB-dead mutants are lacking
10. 2025 Medium

    Identification of ACSL4 as another DUB substrate — stabilized by K48-linked deubiquitination to promote fatty acid biosynthesis in HCC — and BioID proximity mapping in muscle cells revealing nuclear localization and interactions with sarcomeric/lysosomal proteins significantly expanded the known interactome and subcellular distribution of eIF3f.

    Evidence Co-IP and ubiquitination assays with metabolic flux analysis in HCC models; CRISPR-Cas9 endogenous BioID tagging with mass spectrometry and polysome profiling in human muscle cells

    PMID:40154622 PMID:41423661

    Open questions at the time

    • Functional significance of nuclear eIF3f in muscle is unknown
    • How eIF3f selectivity among DUB substrates is determined is not established
    • Whether sarcomeric interactions represent direct binding or proximity within a larger complex is unresolved

• The structural basis of eIF3f's deubiquitinase catalytic mechanism, the logic governing substrate selectivity across its translation-dependent and -independent roles, and the physiological partitioning of eIF3f between the eIF3 complex, mTORC1, and its DUB functions remain open questions.
• No crystal or cryo-EM structure of eIF3f alone or in complex with a DUB substrate exists
• Whether the DUB and translation scaffolding functions are mutually exclusive or concurrent is untested
• Tissue-specific conditional knockout phenotypes beyond muscle are unreported