Prion protein aggresomes are poly(A)+ ribonucleoprotein complexes that induce a PKR-mediated deficient cell stress response.
In mammalian cells, cytoplasmic protein aggregates generally coalesce to form aggresomal particles. Recent studies indicate that prion-infected cells produce prion protein (PrP) aggresomes, and that such aggregates may be present in the brain of infected mice. The molecular activity of PrP aggresomes has not been fully investigated. We report that PrP aggresomes initiate a cell stress response by activating the RNA-dependent protein kinase (PKR). Activated PKR phosphorylates the translation initiation factor eIF2alpha, resulting in protein synthesis shut-off. However, other components of the stress response, including the assembly of poly(A)+ RNA-containing stress granules and the synthesis of heat shock protein 70, are repressed. In situ hybridization experiments and affinity chromatography on oligo(dT)-cellulose showed that PrP aggresomes bind poly(A)+ RNA, and are therefore poly(A)+ ribonucleoprotein complexes. These findings support a model in which PrP aggresomes send neuronal cells into untimely demise by modifying the cell stress response, and by inducing the aggregation of poly(A)+ RNA.
Goggin
Kevin
K
Department of Biochemistry, Faculty of Medicine, University of Sherbrooke, 3001 12(ème) Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4.
Beaudoin
Simon
S
Grenier
Catherine
C
Brown
Andrée-Anne
AA
Roucou
Xavier
X
D000818:Animals; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D011328:Prions / Q000378:metabolism / Q000502:physiology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000502:physiology*
D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D011328:Prions; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D019892:eIF-2 Kinase