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

Abstract

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 Culllin 3-RING ubiquitin ligase complex (CRL3), interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 by catalyzed CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and tumor cell growth both in vivo and in vitro. Moreover, our results 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 mTOR signaling pathway, frequently dysregulated in cancer, represents a promising target for anticancer therapies. IBTK overexpression contributes to cervical cancer tumorigenesis by translation regulation and represents a promising target for anticancer therapies.