METTL16 promotes translation and lung tumorigenesis by sequestering cytoplasmic eIF4E2

Abstract

N⁶-methyladenosine (m⁶A) plays crucial roles in regulating RNA metabolisms. METTL16 identified as a single-component methyltransferase catalyzes m⁶A formation in the nucleus; whether it regulates cytoplasmic RNA fate remains unknown. Here, we detected the dual localization of METTL16 in the nucleus and cytoplasm. METTL16 depletion attenuates protein synthesis, but the methyltransferase activity is not required for its translation-promoting function. Mechanistically, we identified an interactor of METTL16, eIF4E2, which represses translation by acting as a competitor of eIF4E. The METTL16-eIF4E2 interaction impedes the recruitment of eIF4E2 to 5' cap structure, promoting the cap recognition by eIF4E and selective protein synthesis. Depletion of METTL16 suppresses lung tumorigenesis by downregulating the translation of key oncogenes. Collectively, our study reports a role of METTL16 in modulating translation and provides a therapeutic target for lung cancer treatment.

Keywords: CP: Cancer; METTL16; eIF4E2; protein translation; tumorigenesis.