Inhibition of the ubiquitin-proteasome system induces stress granule formation.
The inhibition of the ubiquitin-dependent proteasome system (UPS) via specific drugs is one type of approach used to combat cancer. Although it has been suggested that UPS inhibition prevents the rapid decay of AU-rich element (ARE)-containing messages, very little is known about the cellular mechanisms leading to this effect. Here we establish a link between the inhibition of UPS activity, the formation of cytoplasmic stress granules (SGs), and mRNA metabolism. The assembly of the SGs requires the phosphorylation of the translation initiation factor eIF2alpha by a mechanism involving the stress kinase GCN2. On prolonged UPS inhibition and despite the maintenance of eIF2alpha phosphorylation, SGs disassemble and translation recovers in an Hsp72 protein-dependent manner. The formation of these SGs coincides with the disassembly of processing bodies (PBs), known as mRNA decay entities. As soon as the SGs assemble, they recruit ARE-containing messages such as p21(cip1) mRNA, which are stabilized under these conditions. Hence, our findings suggest that SGs could be considered as one of the players that mediate the early response of the cell to proteasome inhibitors by interfering temporarily with mRNA decay pathways.
Mazroui
Rachid
R
McGill University, Department of Biochemistry, Montreal, Quebec, Canada.
Di Marco
Sergio
S
Kaufman
Randal J
RJ
Gallouzi
Imed-Eddine
IE
D017209:Apoptosis / Q000187:drug effects; D018389:Codon, Nonsense / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D025801:Ubiquitin / Q000037:antagonists & inhibitors*
D018389:Codon, Nonsense; D015852:Eukaryotic Initiation Factor-2; D050884:HSP72 Heat-Shock Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde