Cell chemical biology, 2021-04, Vol.28 (4), p.475-486.e8
2021
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- Autor(en) / Beteiligte
- Titel
- Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A
- Ist Teil von
- Cell chemical biology, 2021-04, Vol.28 (4), p.475-486.e8
- Ort / Verlag
- United States: Elsevier Ltd
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •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 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2451-9456eISSN: 2451-9448, 2451-9456DOI: 10.1016/j.chembiol.2020.11.008Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8052261
- Format
- –
- Schlagworte
- Benzofurans - chemistry, Benzofurans - pharmacology, Cells, Cultured, DDX3, DEAD-box RNA Helicases - antagonists & inhibitors, DEAD-box RNA Helicases - metabolism, dominant negative, eIF4A, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Eukaryotic Initiation Factor-4A - antagonists & inhibitors, Eukaryotic Initiation Factor-4A - metabolism, Female, Humans, Male, Models, Molecular, Molecular Conformation, ribosome, ribosome profiling, RNA, RNA Bind-n-Seq, rocaglate, translation, translation inhibitor