Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

Andreas C Woerner; Frédéric Frottin; Daniel Hornburg; Li R Feng; Felix Meissner; Maria Patra; Jörg Tatzelt; Matthias Mann; Konstanze F Winklhofer; F Ulrich Hartl; Mark S Hipp

doi:10.1126/science.aad2033

Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

Andreas C Woerner, Frédéric Frottin, Daniel Hornburg, Li R Feng, Felix Meissner, Maria Patra, Jörg Tatzelt, Matthias Mann, Konstanze F Winklhofer, F Ulrich Hartl, Mark S Hipp

216 Citationer (Scopus)

Abstract

Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial β-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.

Originalsprog	Engelsk
Tidsskrift	Science (New York, N.Y.)
Vol/bind	351
Udgave nummer	6269
Sider (fra-til)	173-6
Antal sider	4
ISSN	0036-8075
DOI	https://doi.org/10.1126/science.aad2033
Status	Udgivet - 8 jan. 2016
Udgivet eksternt	Ja

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10.1126/science.aad2033

Citationsformater

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title = "Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA",

abstract = "Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial β-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.",

keywords = "Active Transport, Cell Nucleus, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, HEK293 Cells, Humans, Huntingtin Protein, Nerve Tissue Proteins, Neurodegenerative Diseases, Protein Aggregates, Protein Structure, Secondary, RNA, Messenger, Journal Article, Research Support, Non-U.S. Gov't",

author = "Woerner, {Andreas C} and Fr{\'e}d{\'e}ric Frottin and Daniel Hornburg and Feng, {Li R} and Felix Meissner and Maria Patra and J{\"o}rg Tatzelt and Matthias Mann and Winklhofer, {Konstanze F} and Hartl, {F Ulrich} and Hipp, {Mark S}",

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year = "2016",

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doi = "10.1126/science.aad2033",

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TY - JOUR

T1 - Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

AU - Woerner, Andreas C

AU - Frottin, Frédéric

AU - Hornburg, Daniel

AU - Feng, Li R

AU - Meissner, Felix

AU - Patra, Maria

AU - Tatzelt, Jörg

AU - Mann, Matthias

AU - Winklhofer, Konstanze F

AU - Hartl, F Ulrich

AU - Hipp, Mark S

PY - 2016/1/8

Y1 - 2016/1/8

N2 - Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial β-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.

AB - Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial β-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.

KW - Active Transport, Cell Nucleus

KW - Cell Nucleus

KW - Cytoplasm

KW - DNA-Binding Proteins

KW - HEK293 Cells

KW - Humans

KW - Huntingtin Protein

KW - Nerve Tissue Proteins

KW - Neurodegenerative Diseases

KW - Protein Aggregates

KW - Protein Structure, Secondary

KW - RNA, Messenger

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1126/science.aad2033

DO - 10.1126/science.aad2033

M3 - Journal article

C2 - 26634439

SN - 0036-8075

VL - 351

SP - 173

EP - 176

JO - Science

JF - Science

IS - 6269

ER -

Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

Abstract

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