Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Heidi Olzscha; Sonya M. Schermann; Andreas C. Woerner; Stefan Pinkert; Michael H. Hecht; Gian G. Tartaglia; Michele Vendruscolo; Manajit Hayer-Hartl; F. Ulrich Hartl; R. Martin Vabulas

doi:10.1016/j.cell.2010.11.050

Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Heidi Olzscha, Sonya M. Schermann, Andreas C. Woerner, Stefan Pinkert, Michael H. Hecht, Gian G. Tartaglia, Michele Vendruscolo, Manajit Hayer-Hartl, F. Ulrich Hartl, R. Martin Vabulas

Research output: Contribution to journal › Article › peer-review

558 Scopus citations

Abstract

Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions. PaperFlick:

Original language	English (US)
Pages (from-to)	67-78
Number of pages	12
Journal	Cell
Volume	144
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2010.11.050
State	Published - Jan 7 2011

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

Keywords

CELLBIO
HUMDISEASE

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10.1016/j.cell.2010.11.050

Cite this

@article{88ecd884d42b438090cb62072b3efd53,

title = "Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions",

abstract = "Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions. PaperFlick:",

keywords = "CELLBIO, HUMDISEASE",

author = "Heidi Olzscha and Schermann, {Sonya M.} and Woerner, {Andreas C.} and Stefan Pinkert and Hecht, {Michael H.} and Tartaglia, {Gian G.} and Michele Vendruscolo and Manajit Hayer-Hartl and Hartl, {F. Ulrich} and Vabulas, {R. Martin}",

note = "Funding Information: We thank C.G. Glabe for providing the A11 antibody and H. Wagner for plasmids HSP70-Luc and NF-κB-Luc. We acknowledge the help of H. Engelhardt with FTIR measurements, technical assistance by O. Mihalache and V. Marcus with electron microscopy, and R. Zenke (MPIB core facility) for confocal microscopy. Financial support from EU Framework 7 Integrated Project PROSPECTS, the Deutsche Forschungsgemeinschaft (SFB 596), the Ernst-Jung Foundation, and the K{\"o}rber Foundation is acknowledged. H.O. and A.W. have a fellowship from the Fonds der Chemischen Industrie, and H.O. is supported by the Elite Graduate Network of Bavaria. ",

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doi = "10.1016/j.cell.2010.11.050",

language = "English (US)",

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AU - Olzscha, Heidi

AU - Schermann, Sonya M.

AU - Woerner, Andreas C.

AU - Pinkert, Stefan

AU - Hecht, Michael H.

AU - Tartaglia, Gian G.

AU - Vendruscolo, Michele

AU - Hayer-Hartl, Manajit

AU - Hartl, F. Ulrich

AU - Vabulas, R. Martin

N1 - Funding Information: We thank C.G. Glabe for providing the A11 antibody and H. Wagner for plasmids HSP70-Luc and NF-κB-Luc. We acknowledge the help of H. Engelhardt with FTIR measurements, technical assistance by O. Mihalache and V. Marcus with electron microscopy, and R. Zenke (MPIB core facility) for confocal microscopy. Financial support from EU Framework 7 Integrated Project PROSPECTS, the Deutsche Forschungsgemeinschaft (SFB 596), the Ernst-Jung Foundation, and the Körber Foundation is acknowledged. H.O. and A.W. have a fellowship from the Fonds der Chemischen Industrie, and H.O. is supported by the Elite Graduate Network of Bavaria.

PY - 2011/1/7

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N2 - Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions. PaperFlick:

AB - Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions. PaperFlick:

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Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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