TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA

Mei Xia Che; Lei Lei Jiang; Hai Yin Li; Ya Jun Jiang; Hong Yu Hu

doi:10.1016/j.febslet.2015.06.009

TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA

Mei Xia Che, Lei Lei Jiang, Hai Yin Li, Ya Jun Jiang, Hong Yu Hu

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

28 Scopus citations

Abstract

Abstract TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.

Original language	English (US)
Article number	37221
Pages (from-to)	1920-1928
Number of pages	9
Journal	FEBS Letters
Volume	589
Issue number	15
DOIs	https://doi.org/10.1016/j.febslet.2015.06.009
State	Published - Jul 3 2015

Bibliographical note

Funding Information:
This work was supported by National Basic Research Program of China (Grants 2012CB911003 and 2011CB911104 ) and National Natural Science Foundation of China (Grant 31270773 ).

Publisher Copyright:
© 2015 Federation of European Biochemical Societies.

Keywords

C-terminal fragment of ∼35kDa
Cytoplasmic inclusion
RNA recognition motif
Sequestration
TAR DNA binding protein of 43kDa

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title = "TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA",

abstract = "Abstract TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.",

keywords = "C-terminal fragment of ∼35kDa, Cytoplasmic inclusion, RNA recognition motif, Sequestration, TAR DNA binding protein of 43kDa",

author = "Che, {Mei Xia} and Jiang, {Lei Lei} and Li, {Hai Yin} and Jiang, {Ya Jun} and Hu, {Hong Yu}",

note = "Funding Information: This work was supported by National Basic Research Program of China (Grants 2012CB911003 and 2011CB911104 ) and National Natural Science Foundation of China (Grant 31270773 ). Publisher Copyright: {\textcopyright} 2015 Federation of European Biochemical Societies.",

year = "2015",

month = jul,

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doi = "10.1016/j.febslet.2015.06.009",

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T1 - TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA

AU - Che, Mei Xia

AU - Jiang, Lei Lei

AU - Li, Hai Yin

AU - Jiang, Ya Jun

AU - Hu, Hong Yu

N1 - Funding Information: This work was supported by National Basic Research Program of China (Grants 2012CB911003 and 2011CB911104 ) and National Natural Science Foundation of China (Grant 31270773 ). Publisher Copyright: © 2015 Federation of European Biochemical Societies.

PY - 2015/7/3

Y1 - 2015/7/3

N2 - Abstract TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.

AB - Abstract TDP-43 (TAR DNA binding protein of 43kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.

KW - C-terminal fragment of ∼35kDa

KW - Cytoplasmic inclusion

KW - RNA recognition motif

KW - Sequestration

KW - TAR DNA binding protein of 43kDa

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TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA

Abstract

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