Abstract
Increasing evidence indicates the existence of selective autophagy pathways, but the manner in which substrates are recognized and targeted to the autophagy system is poorly understood. One strategy is transport of a particular substrate to the aggresome, a perinuclear compartment with high autophagic activity. In this paper, we identify a new cellular pathway that uses the specificity of heat-shock protein 70 (Hsp70) to misfolded proteins as the basis for aggresome-targeting and autophagic degradation. This pathway is regulated by the stress-induced co-chaperone Bcl-2-associated athanogene 3 (BAG3), which interacts with the microtubule-motor dynein and selectively directs Hsp70 substrates to the motor and thereby to the aggresome. Notably, aggresome-targeting by BAG3 is distinct from previously described mechanisms, as it does not depend on substrate ubiquitination.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Apoptosis Regulatory Proteins
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Autophagy*
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COS Cells
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Chlorocebus aethiops
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Dyneins / metabolism
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Green Fluorescent Proteins / genetics
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HEK293 Cells
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HSP70 Heat-Shock Proteins / metabolism*
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Humans
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Inclusion Bodies / metabolism
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Inclusion Bodies / ultrastructure
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Mice
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Mice, Transgenic
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Motor Neurons / metabolism
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Point Mutation
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Proteasome Inhibitors
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Protein Folding
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Protein Transport
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism*
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Sequence Deletion
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Spinal Cord / cytology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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BAG3 protein, human
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HSP70 Heat-Shock Proteins
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Proteasome Inhibitors
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Superoxide Dismutase
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Dyneins