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15. mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3 IBTK -mediated ubiquitination of eIF4A1 in cancer cells.

Author

Jiao D, Sun H, Zhao X, Chen Y, Lv Z, Shi Q, Li Y, Wang C, and Gao K

Subjects
Animals, Humans, Mice, Cell Line, Tumor, Eukaryotic Initiation Factor-4A metabolism, Eukaryotic Initiation Factor-4A genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 1 genetics, Protein Biosynthesis, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Ribosomal Protein S6 Kinases, 70-kDa genetics, Signal Transduction, Ubiquitination
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 the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3 IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical 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 CRL3 IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies., Competing Interests: DJ, HS, XZ, YC, ZL, QS, YL, CW, KG No competing interests declared, (© 2023, Jiao, Sun et al.)

Published
2024
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