title: TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress.
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.
authors: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. higashi-sj@igakuken.or.jp
authors: Shinji
authors: S
authors: Higashi
authors: Tomohiro
authors: T
authors: Kabuta
authors: Yoshitaka
authors: Y
authors: Nagai
authors: Yukihiro
authors: Y
authors: Tsuchiya
authors: Haruhiko
authors: H
authors: Akiyama
authors: Keiji
authors: K
authors: Wada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018053:Arsenites / Q000494:pharmacology; D020170:Caspase 1; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D017670:Sodium Compounds / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018053:Arsenites; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D017670:Sodium Compounds; C017947:sodium arsenite; D048031:JNK Mitogen-Activated Protein Kinases; D020170:Caspase 1
keywords: TDP-43; amyotrophic lateral sclerosis; apoptosis; frontotemporal lobar degeneration; oxidative stress; stress granule