Structural determinants of the cellular localization and shuttling of TDP-43

Youhna M. Ayala, Paola Zago, Andrea D'Ambrogio, Ya F. Xu, Leonard Petrucelli, Emanuele Buratti, Francisco E. Baralle

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

TDP-43 (also known as TARDBP) regulates different processes of gene expression, including transcription and splicing, through RNA and DNA binding. Moreover, recent reports have shown that the protein interacts with the 3′ UTRs of specific mRNAs. The aberrant cellular distribution and aggregation of TDP-43 were recently reported in neurodegenerative diseases, namely frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A detailed description of the determinants for cellular localization has yet to emerge, including information on how the known functions of TDP-43 and cellular targeting affect each other. We provide the first experimental evidence that TDP-43 continuously shuttles between nucleus and cytoplasm in a transcription-dependent manner. Furthermore, we investigate the role of the functional TDP-43 domains in determining cellular targeting through a combination of immunofluorescence and biochemical fractionation methods. Our analyses indicate that the C-terminus is essential for solubility and cellular localization, because its deletion results in the formation of large nuclear and cytoplasmic aggregates. Disruption of the RNA-recognition domain required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in the nucleoplasm. Our findings suggest that TDP-43 solubility and localization are particularly sensitive to disruptions that extend beyond the newly found nuclear localization signal and depend on a combination of factors that are closely connected to the functional properties of this protein.

Original languageEnglish (US)
Pages (from-to)3778-3785
Number of pages8
JournalJournal of Cell Science
Volume121
Issue number22
DOIs
StatePublished - Nov 15 2008

Fingerprint

Solubility
Frontotemporal Lobar Degeneration
RNA
RNA Splicing
Nuclear Localization Signals
DNA
Amyotrophic Lateral Sclerosis
3' Untranslated Regions
Neurodegenerative Diseases
Fluorescent Antibody Technique
Cytoplasm
Proteins
Gene Expression
Messenger RNA

Keywords

  • hnRNP
  • Nuclear-cytoplasmic shuttling
  • RNA recognition motifs

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ayala, Y. M., Zago, P., D'Ambrogio, A., Xu, Y. F., Petrucelli, L., Buratti, E., & Baralle, F. E. (2008). Structural determinants of the cellular localization and shuttling of TDP-43. Journal of Cell Science, 121(22), 3778-3785. https://doi.org/10.1242/jcs.038950

Structural determinants of the cellular localization and shuttling of TDP-43. / Ayala, Youhna M.; Zago, Paola; D'Ambrogio, Andrea; Xu, Ya F.; Petrucelli, Leonard; Buratti, Emanuele; Baralle, Francisco E.

In: Journal of Cell Science, Vol. 121, No. 22, 15.11.2008, p. 3778-3785.

Research output: Contribution to journalArticle

Ayala, YM, Zago, P, D'Ambrogio, A, Xu, YF, Petrucelli, L, Buratti, E & Baralle, FE 2008, 'Structural determinants of the cellular localization and shuttling of TDP-43', Journal of Cell Science, vol. 121, no. 22, pp. 3778-3785. https://doi.org/10.1242/jcs.038950
Ayala, Youhna M. ; Zago, Paola ; D'Ambrogio, Andrea ; Xu, Ya F. ; Petrucelli, Leonard ; Buratti, Emanuele ; Baralle, Francisco E. / Structural determinants of the cellular localization and shuttling of TDP-43. In: Journal of Cell Science. 2008 ; Vol. 121, No. 22. pp. 3778-3785.
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