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.
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
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