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U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy.

Journal of neurochemistry | Oct 27, 2004

http://www.ncbi.nlm.nih.gov/pubmed/15447663

Neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated and ubiquitylated tau, are exhibited at regions where neuronal loss occurs in neurodegenerative diseases; however, the mechanisms of NFT formation remain unknown. Molecular studies of frontotemporal dementia with parkinsonism-17 demonstrated that increasing the ratio of tau with exon 10 insertion induced fibrillar tau accumulation. Here, we show that carboxyl terminus of Hsc70-interacting protein (CHIP), a U-box protein, recognizes the microtubule-binding repeat region of tau and preferentially ubiquitylates four-repeat tau compared with three-repeat tau. Overexpression of CHIP induced the prompt degradation of tau, reduced the formation of detergent-insoluble tau and inhibited proteasome inhibitor-induced cell death. NFT bearing neurons in progressive supranuclear palsy, in which four-repeat tau is a component, showed the accumulation of CHIP. Thus, CHIP is a ubiquitin ligase for four-repeat tau and maintains neuronal survival by regulating the quality control of tau in neurons.

Pubmed ID: 15447663 RIS Download

Mesh terms: Animals | Cell Death | Cell Line | Cell Survival | Cercopithecus aethiops | Cysteine Endopeptidases | Enzyme Inhibitors | HSC70 Heat-Shock Proteins | HSP70 Heat-Shock Proteins | Humans | Mice | Multienzyme Complexes | Mutagenesis, Site-Directed | Neurons | Proteasome Endopeptidase Complex | Protein Binding | RNA Interference | Recombinant Fusion Proteins | Repetitive Sequences, Amino Acid | Sequence Deletion | Tauopathies | Transfection | Ubiquitin | Ubiquitin-Protein Ligases | tau Proteins

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