Inhibition of Nonsense-mediated mRNA Decay by the Natural Product Pateamine A through Eukaryotic Initiation Factor 4AIII

Nonsense-mediated mRNA decay (NMD) in mammalian cells is a key mechanism for the removal of mRNA containing premature stop codons and is mediated by the coordinated function of numerous proteins that dynamically associate with the exon junction complex. The information communicated by these interact...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-08, Vol.284 (35), p.23613-23621
Main Authors: Dang, Yongjun, Low, Woon-Kai, Xu, Jing, Gehring, Niels H., Dietz, Harry C., Romo, Daniel, Liu, Jun O.
Format: Article
Language:English
Subjects:
Biological Products - chemistry
Cell Line
Codon, Nonsense - genetics
Codon, Nonsense - metabolism
Down-Regulation - drug effects
Epoxy Compounds - pharmacology
Eukaryotic Initiation Factors - genetics
Eukaryotic Initiation Factors - metabolism
Humans
Macrolides - pharmacology
Peptide Chain Initiation, Translational - drug effects
Protein Binding - drug effects
RNA Stability - drug effects
RNA, Messenger - chemistry
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA: Processing and Catalysis
Thiazoles - pharmacology
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Summary:Nonsense-mediated mRNA decay (NMD) in mammalian cells is a key mechanism for the removal of mRNA containing premature stop codons and is mediated by the coordinated function of numerous proteins that dynamically associate with the exon junction complex. The information communicated by these interactions and the functional consequences from a mechanistic perspective, however, are not completely documented. Herein, we report that the natural product pateamine A (PatA) is capable of inhibiting NMD through direct interaction with eIF4AIII, which is independent of its inhibition of translation initiation. Furthermore, we have characterized the mechanisms by which PatA and cycloheximide modulate NMD. Unlike CHX, PatA was found to inhibit NMD by a novel mechanism that is independent of the phosphorylation of Up-frameshift protein 1.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.009985