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- Title
TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress.
- Authors
Higashi, Shinji; Kabuta, Tomohiro; Nagai, Yoshitaka; Tsuchiya, Yukihiro; Akiyama, Haruhiko; Wada, Keiji
- Abstract
TAR DNA-binding protein 43 (TDP-43) has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. To understand the physiological roles of TDP-43 in the complex translational regulation mechanisms, we exposed cultured cells to oxidative stress induced by sodium arsenite (ARS) for different periods of time, leading to non-lethal or sublethal injury. Polysome profile analysis revealed that ARS-induced stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA, which was not found under the steady-state condition. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs); this association was transient because it was immediately dissolved by the removal of the stress. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, biochemical alterations of TDP-43, such as increased insolubility and disulfide bond formation, were irreversible. TDP-43 was finally phosphorylated via the ARS-induced c-jun N-terminal kinase pathway. In TDP-43-silenced cells, stalled mRNA and poly (A)+ RNA stability was disturbed and cytotoxicity increased under sublethal stress. Thus, TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress.
- Subjects
DNA-binding proteins; SODIUM arsenite; AMYOTROPHIC lateral sclerosis; FRONTOTEMPORAL dementia; OXIDATIVE stress; RIBOSOMES; MESSENGER RNA
- Publication
Journal of Neurochemistry, 2013, Vol 126, Issue 2, p288
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.12194