Abstract
In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Autophagy
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Female
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Histone Deacetylase 6
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Histone Deacetylases / metabolism*
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Humans
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Inclusion Bodies / metabolism*
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Lysosomes / metabolism
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Male
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Mice
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Mice, Inbred C3H
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Interaction Mapping
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Protein Transport
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Proteolysis
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Sequestosome-1 Protein
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitinated Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Tripartite Motif Proteins
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Ubiquitinated Proteins
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TRIM50 protein, human
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Ubiquitin-Protein Ligases
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases