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 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.
Dang
Yongjun
Y
Department of Pharmacology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Low
Woon-Kai
WK
Xu
Jing
J
Gehring
Niels H
NH
Dietz
Harry C
HC
Romo
Daniel
D
Liu
Jun O
JO
D001688:Biological Products / Q000737:chemistry; D002460:Cell Line; D018389:Codon, Nonsense / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology*; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
D001688:Biological Products; D018389:Codon, Nonsense; D004852:Epoxy Compounds; D039642:Eukaryotic Initiation Factors; D018942:Macrolides; D012333:RNA, Messenger; D013844:Thiazoles; C421324:pateamine A