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

•TDP-35 is the 35kDa fragment of TDP-43 that forms cytoplasmic inclusions.•The TDP-35 inclusions sequester full-length TDP-43 through binding with RNA.•RNA recognition motif 1 plays a dominant role in nucleic-acid binding.•Sequestration of TDP-43 by the TDP-35 inclusions is implicated in the TDP-43...

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Bibliographic Details
Published in:FEBS letters 2015-07, Vol.589 (15), p.1920-1928
Main Authors: Che, Mei-Xia, Jiang, Lei-Lei, Li, Hai-Yin, Jiang, Ya-Jun, Hu, Hong-Yu
Format: Article
Language:English
Subjects:
ALS
amyotrophic lateral sclerosis
Base Sequence
C-terminal fragment of ∼35kDa
Cytoplasm - metabolism
Cytoplasmic inclusion
deoxyribonuclease
DNA Primers
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNase
FISH
fluorescent in situ hybridization
frontotemporal lobar degeneration
FTLD
GFP
green fluorescent protein
HEK293 Cells
Humans
immunofluorescence
isothermal titration calorimetry
ITC
Mutation
Peptide Fragments - genetics
Peptide Fragments - physiology
Polymerase Chain Reaction
Protein Binding
ribonuclease A
ribonucleoprotein
RIP
RNA - genetics
RNA - metabolism
RNA immunoprecipitation
RNA recognition motif
RNase A
RNP
RRM
Sequestration
single-strand DNA
ssDNA
TAR DNA binding protein of 43kDa
TDP-35
TDP-43
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Summary:•TDP-35 is the 35kDa fragment of TDP-43 that forms cytoplasmic inclusions.•The TDP-35 inclusions sequester full-length TDP-43 through binding with RNA.•RNA recognition motif 1 plays a dominant role in nucleic-acid binding.•Sequestration of TDP-43 by the TDP-35 inclusions is implicated in the TDP-43 proteinopathy. 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.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2015.06.009