
The mTORC1/S6K1 signaling pathway promotes sustained oncogenic translation by enhancing IBTK-mediated non-degradative ubiquitination of eIF4A1, a crucial subunit of the eIF4F complex.


coremsg

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and tumor cell growth both in vivo and in vitro . Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.

Statement of Significance: Overexpression of IBTK contributes to the process of tumorigenesis by amplifying translation, and represents a promising target for anti-cancer therapies.

### Competing Interest Statement

The authors have declared no competing interest.

*   eIFs
    :   eukaryotic initiation factors
    CRL3
    :   Cullin 3-RING ubiquitin ligase
    EJC
    :   exon junction complex
    S6Ks
    :   S6 kinases
    IBTK
    :   the Inhibitor of Bruton’s tyrosine kinase
    CCK-8
    :   Cell Counting Kit-8
    PI
    :   propidium iodide
    BioID
    :   biotinylation identification
    DOX
    :   doxycycline
    SGs
    :   stress granules
    AS
    :   sodium arsenite
    WCLs
    :   whole cell lysates
    PFA
    :   paraformaldehyde
    ATCC
    :   American Type Culture Collection
    WT
    :   Wild-Type
    RT-qPCR
    :   Quantitative reverse transcription polymerase chain reaction
    IHC
    :   Immunohistochemistry
    IP
    :   Immunoprecipitation

mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated non-degradative ubiquitination of eIF4A1

regulation-of-oncogenic-translation-by-the-mtorc1-s6k1-ibtk-eif4a1-signaling-axis


Regulation of Oncogenic Translation by the mTORC1/S6K1-IBTK-eIF4A1 Signaling Axis
