Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A. Issue 4 (15th April 2021)

• Record Type: Journal Article
• Authors: Chen, Mingming; Asanuma, Miwako; Takahashi, Mari; Shichino, Yuichi; Mito, Mari; Fujiwara, Koichi; Saito, Hironori; Floor, Stephen N.; Ingolia, Nicholas T.; Sodeoka, Mikiko; Dodo, Kosuke; Ito, Takuhiro; Iwasaki, Shintaro
• Is Part Of: Cell chemical biology. Volume 28:Issue 4(2021)
• Page Start: 475
• Page End: 486.e8
• Publication Date: 2021-04-15
• Subjects: RNA -- ribosome -- rocaglate -- translation -- translation inhibitor -- ribosome profiling -- eIF4A -- DDX3 -- dominant negative -- RNA Bind-n-Seq; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.11.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: The translation inhibitor rocaglamide A (RocA) has shown promising antitumor activity because it uniquely clamps eukaryotic initiation factor (eIF) 4A onto polypurine RNA for selective translational repression. As eIF4A has been speculated to be a unique target of RocA, alternative targets have not been investigated. Here, we reveal that DDX3 is another molecular target of RocA. Proximity-specific fluorescence labeling of an O -nitrobenzoxadiazole-conjugated derivative revealed that RocA binds to DDX3. RocA clamps the DDX3 protein onto polypurine RNA in an ATP-independent manner. Analysis of a de novo -assembled transcriptome from the plant Aglaia, a natural source of RocA, uncovered the amino acid critical for RocA binding. Moreover, ribosome profiling showed that because of the dominant-negative effect of RocA, high expression of eIF4A and DDX3 strengthens translational repression in cancer cells. This study indicates that sequence-selective clamping of DDX3 and eIF4A, and subsequent dominant-negative translational repression by RocA determine its tumor toxicity. Graphical abstract: Highlights: RocA clamps DDX3 on polypurine sequences in an ATP-independent manner Gln360 in DDX3 is a critical residue for RocA binding RocA⋅DDX3 complex inhibits protein synthesis in a dominant-negative manner eIF4A and DDX3 abundance correlates with RocA sensitivity in cancer cells Abstract : Chen et al. demonstrated the translation inhibitor rocaglamide A (RocA) alternatively targets DDX3, in addition to eIF4A. As RocA converts DDX3 and eIF4A into dominant-negative translational repressors, the abundance of those proteins in cells is an indicator of RocA sensitivity.