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 |
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Authors: | Hatakeyama Shigetsugu Matsumoto Masaki Kamura Takumi Murayama Miyuki Chui Du-Hua Planel Emmanuel Takahashi Ryosuke Nakayama Keiichi I Takashima Akihiko |
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Affiliation: | Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Fukuoka, Japan. |
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Abstract: | 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. |
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Keywords: | carboxyl terminus of Hsc70‐interacting protein neurodegeneration neurofibrillary tangle tau ubiquitylation |
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