Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA
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Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. / Woerner, Andreas C; Frottin, Frédéric; Hornburg, Daniel; Feng, Li R; Meissner, Felix; Patra, Maria; Tatzelt, Jörg; Mann, Matthias; Winklhofer, Konstanze F; Hartl, F Ulrich; Hipp, Mark S.
In: Science (New York, N.Y.), Vol. 351, No. 6269, 08.01.2016, p. 173-6.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - Copyright © 2016, American Association for the Advancement of Science.
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
VL - 351
SP - 173
EP - 176
JO - Science
JF - Science
SN - 0036-8075
IS - 6269
ER -
ID: 186877743