1. Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones.
- Author
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Constantinescu P, Brown RA, Wyatt AR, Ranson M, and Wilson MR
- Subjects
- Amino Acid Substitution, Animals, Cell Line, Cell Survival drug effects, Clusterin chemistry, Clusterin metabolism, Conalbumin chemistry, Conalbumin metabolism, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Endothelium, Vascular ultrastructure, Fibrinolysin antagonists & inhibitors, Fibrinolysin chemistry, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Microglia metabolism, Microglia pathology, Microglia ultrastructure, Mutation, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Plasminogen chemistry, Plasminogen metabolism, Plasminogen Activators chemistry, Plasminogen Activators genetics, Plasminogen Activators metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Solubility, Superoxide Dismutase-1 chemistry, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Tissue Plasminogen Activator chemistry, Fibrinolysin metabolism, Microglia drug effects, Peptide Fragments toxicity, Plasminogen Activators toxicity, Protein Aggregates, Tissue Plasminogen Activator metabolism, alpha-2-Antiplasmin metabolism
- Abstract
The misfolding of proteins and their accumulation in extracellular tissue compartments as insoluble amyloid or amorphous protein aggregates are a hallmark feature of many debilitating protein deposition diseases such as Alzheimer's disease, prion diseases, and type II diabetes. The plasminogen activation system is best known as an extracellular fibrinolytic system but was previously reported to also be capable of degrading amyloid fibrils. Here we show that amorphous protein aggregates interact with tissue-type plasminogen activator and plasminogen, via an exposed lysine-dependent mechanism, to efficiently generate plasmin. The insoluble aggregate-bound plasmin is shielded from inhibition by α
2 -antiplasmin and degrades amorphous protein aggregates to release smaller, soluble but relatively hydrophobic fragments of protein (plasmin-generated protein fragments (PGPFs)) that are cytotoxic. In vitro , both endothelial and microglial cells bound and internalized PGPFs before trafficking them to lysosomes. Clusterin and α2 -macroglobulin bound to PGPFs to significantly ameliorate their toxicity. On the basis of these findings, we hypothesize that, as part of the in vivo extracellular proteostasis system, the plasminogen activation system may work synergistically with extracellular chaperones to safely clear large and otherwise pathological protein aggregates from the body., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2017
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