The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain
| Autor: | Paola Pietroni, David M. Roberts, Rasmus Hartmann-Petersen, Jonathan Cook, Nishi Vasisht, Robert A. Spooner, Lynne M. Roberts, J. Michael Lord |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
ATPase
viruses DSS disuccinimidyl suberate Endoplasmic Reticulum ricin A chain BFA brefeldin A Biochemistry Ribosome ERAD ER-associated degradation chemistry.chemical_compound nnRTA non-native forms of RTA cLβ-l clasto lactacystin β-lactone chaperone endoplasmic reticulum dislocation QD 0303 health sciences GdnHCl guanidinium chloride biology 030302 biochemistry & molecular biology Caseins AAA ATPase associated with various cellular activities Ricin RP regulatory particle RTA ricin toxin A chain Signal Transduction Research Article Proteasome Endopeptidase Complex Saccharomyces cerevisiae Endocytosis ER endoplasmic reticulum 03 medical and health sciences Pi1 proteasome inhibitor 1 Animals Humans Molecular Biology AAA-ATPase 030304 developmental biology Rpt subunit ALLN N-acetyl-L-leucyl-L-leucylnorleucinal Endoplasmic reticulum Cell Biology CP core particle biochemical phenomena metabolism and nutrition Cytosol proteasome chemistry Proteasome Chaperone (protein) biology.protein Cattle HeLa Cells |
| Zdroj: | Biochemical Journal |
| ISSN: | 0264-6021 |
| Popis: | The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the ER (endoplasmic reticulum) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show in the present study that the proteasome has a more complex role in ricin intoxication than previously recognized, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA (ATPase associated with various cellular activities)-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. The results of the present study implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated. |
| Databáze: | OpenAIRE |
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