Structural determinants of the cellular localization and shuttling of TDP-43
Author:
Ayala Youhna M.1, Zago Paola1, D'Ambrogio Andrea1, Xu Ya-Fei2, Petrucelli Leonard2, Buratti Emanuele1, Baralle Francisco E.1
Affiliation:
1. International Centre for Genetic Engineering and Biotechnology (ICGEB), 34012 Trieste, Italy 2. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
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.
Publisher
The Company of Biologists
Reference35 articles.
1. Abhyankar, M. M., Urekar, C. and Reddi, P. P. (2007). A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: role for TDP-43 in insulator function. J. Biol. Chem.282, 36143-36154. 2. Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y. et al. (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun.351, 602-611. 3. Arrisi-Mercado, P., Romano, M., Muro, A. F. and Baralle, F. E. (2004). An exonic splicing enhancer offsets the atypical GU-rich 3′ splice site of human apolipoprotein A-II exon 3. J. Biol. Chem.279, 39331-39339. 4. Ayala, Y. M., Pantano, S., D'Ambrogio, A., Buratti, E., Brindisi, A., Marchetti, C., Romano, M. and Baralle, F. E. (2005). Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J. Mol. Biol.348, 575-588. 5. Ayala, Y. M., Pagani, F. and Baralle, F. E. (2006). TDP43 depletion rescues aberrant CFTR exon 9 skipping. FEBS Lett.580, 1339-1344.
Cited by
473 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|