Loss-of-function cancer-linked mutations in the EIF4G2 non-canonical translation initiation factor

Sara Meril, Marcela Bahlsen, Miriam Eisenstein, Alon Savidor, Yishai Levin, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Tumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed because of cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site (IRES)- and uORF-dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here, we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein–protein interactions and, importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near-complete loss of function. Two other mutations within the MIF4G domain specifically affected EIF4G2’s ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure–function of EIF4G2 and its potential tumor suppressor effects.

Original languageEnglish
Article numbere202302338
JournalLife Science Alliance
Volume7
Issue number3
DOIs
StatePublished - Mar 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023Meril et al.

Funding

We would like to thank Nadav Goldberg for his advice and many fruitful discussions and Lital Povodovski for preparing the HEK293T EIF4G2 KO cells. This research was supported by a grant from the Pasteur-Weizmann Council and from the Institut Pasteur and the Weizmann Institute of Science.

FundersFunder number
Pasteur-Weizmann Council
Weizmann Institute of Science
Institut Pasteur

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