Chaperone-dependent amyloid assembly protects cells from prion toxicity

@article{citeulike:2819488, abstract = {Protein conformational diseases are associated with the aberrant accumulation of amyloid protein aggregates, but whether amyloid formation is cytotoxic or protective is unclear. To address this issue, we investigated a normally benign amyloid formed by the yeast prion [RNQ+]. Surprisingly, modest overexpression of Rnq1 protein was deadly, but only when preexisting Rnq1 was in the [RNQ+] prion conformation. Molecular chaperones protect against protein aggregation diseases and are generally believed to do so by solubilizing their substrates. The Hsp40 chaperone, Sis1, suppressed Rnq1 proteotoxicity, but instead of blocking Rnq1 protein aggregation, it stimulated conversion of soluble Rnq1 to [RNQ+] amyloid. Furthermore, interference with Sis1-mediated [RNQ+] amyloid formation exacerbated Rnq1 toxicity. These and other data establish that even subtle changes in the folding homeostasis of an amyloidogenic protein can create a severe proteotoxic gain-of-function phenotype and that chaperone-mediated amyloid assembly can be cytoprotective. The possible relevance of these findings to other phenomena, including prion-driven neurodegenerative diseases and heterokaryon incompatibility in fungi, is discussed. 10.1073/pnas.0802593105}, author = {Douglas, Peter M. and Treusch, Sebastian and Ren, Hong-Yu and Halfmann, Randal and Duennwald, Martin L. and Lindquist, Susan and Cyr, Douglas M. }, citeulike-article-id = {2819488}, doi = {http://dx.doi.org/10.1073/pnas.0802593105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {amyloid, chaperone, clip}, month = {May}, number = {20}, pages = {7206--7211}, posted-at = {2008-06-19 06:38:58}, priority = {2}, title = {Chaperone-dependent amyloid assembly protects cells from prion toxicity}, url = {http://dx.doi.org/10.1073/pnas.0802593105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2819488 L3 - citeulike-article-id:2819488 TI - Chaperone-dependent amyloid assembly protects cells from prion toxicity JF - Proceedings of the National Academy of Sciences VL - 105 IS - 20 SP - 7206 EP - 7211 N2 - Protein conformational diseases are associated with the aberrant accumulation of amyloid protein aggregates, but whether amyloid formation is cytotoxic or protective is unclear. To address this issue, we investigated a normally benign amyloid formed by the yeast prion [RNQ+]. Surprisingly, modest overexpression of Rnq1 protein was deadly, but only when preexisting Rnq1 was in the [RNQ+] prion conformation. Molecular chaperones protect against protein aggregation diseases and are generally believed to do so by solubilizing their substrates. The Hsp40 chaperone, Sis1, suppressed Rnq1 proteotoxicity, but instead of blocking Rnq1 protein aggregation, it stimulated conversion of soluble Rnq1 to [RNQ+] amyloid. Furthermore, interference with Sis1-mediated [RNQ+] amyloid formation exacerbated Rnq1 toxicity. These and other data establish that even subtle changes in the folding homeostasis of an amyloidogenic protein can create a severe proteotoxic gain-of-function phenotype and that chaperone-mediated amyloid assembly can be cytoprotective. The possible relevance of these findings to other phenomena, including prion-driven neurodegenerative diseases and heterokaryon incompatibility in fungi, is discussed. 10.1073/pnas.0802593105 KW - amyloid KW - chaperone KW - clip AU - Douglas, Peter AU - Treusch, Sebastian AU - Ren, Hong-Yu AU - Halfmann, Randal AU - Duennwald, Martin AU - Lindquist, Susan AU - Cyr, Douglas PY - 2008/05/20/ UR - http://dx.doi.org/10.1073/pnas.0802593105 ER -