Eukaryotic initiation factor 2alpha-independent pathway of stress granule induction by the natural product pateamine A.
Stress granules are aggregates of small ribosomal subunits, mRNA, and numerous associated RNA-binding proteins that include several translation initiation factors. Stress granule assembly occurs in the cytoplasm of higher eukaryotic cells under a wide variety of stress conditions, including heat shock, UV irradiation, hypoxia, and exposure to arsenite. Thus far, a unifying principle of eukaryotic initiation factor 2alpha phosphorylation prior to stress granule formation has been observed from the majority of experimental evidence. Pateamine A, a natural product isolated from marine sponge, was recently reported to inhibit eukaryotic translation initiation and induce the formation of stress granules. In this report, the protein composition and fundamental progression of stress granule formation and disassembly induced by pateamine A was found to be similar to that for arsenite. However, pateamine A-induced stress granules were more stable and less prone to disassembly than those formed in the presence of arsenite. Most significantly, pateamine A induced stress granules independent of eukaryotic initiation factor 2alpha phosphorylation, suggesting an alternative mechanism of formation from that previously described for other cellular stresses. Taking into account the known inhibitory effect of pateamine A on eukaryotic translation initiation, a model is proposed to account for the induction of stress granules by pateamine A as well as other stress conditions through perturbation of any steps prior to the rejoining of the 60S ribosomal subunit during the entire translation initiation process.
Dang
Yongjun
Y
Department of Pharmacology and Molecular Sciences, Solomon H. Snyder Department of Neuroscience, and Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Kedersha
Nancy
N
Low
Woon-Kai
WK
Romo
Daniel
D
Gorospe
Myriam
M
Kaufman
Randal
R
Anderson
Paul
P
Liu
Jun O
JO
D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology*; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000187:drug effects; D019085:Fluorescent Antibody Technique, Direct; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D012516:Osteosarcoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D018053:Arsenites; D001688:Biological Products; D015415:Biomarkers; D004852:Epoxy Compounds; D015852:Eukaryotic Initiation Factor-2; D018942:Macrolides; D012333:RNA, Messenger; D013844:Thiazoles; C421324:pateamine A