title: The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity.
abstract: TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although the overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. Here we identify Asp174 as a cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that the endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43.
authors: Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Quan
authors: Q
authors: Li
authors: Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Moe
authors: M
authors: Yokoshi
authors: Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hitomi
authors: H
authors: Okada
authors: Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yukio
authors: Y
authors: Kawahara
mesh_terms: D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012995:Solubility
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D010455:Peptides; D066329:Protein Aggregates; D001224:Aspartic Acid; C093516:CASP4 protein, human; D053471:Caspases, Initiator