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Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones

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posted on 2024-11-16, 03:42 authored by Patrick Constantinescu, Rebecca Brown, Amy Wyatt, Marie RansonMarie Ranson, Mark WilsonMark Wilson
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 α2-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.

Funding

The role of clusterin in preventing atherosclerosis

National Health and Medical Research Council

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Defining systems that clear dangerous misfolded proteins from body fluids

Australian Research Council

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History

Citation

Constantinescu, P., Brown, R. A., Wyatt, A. R., Ranson, M. & Wilson, M. R. (2017). Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones. Journal Of Biological Chemistry, 292 (35), 14425-14437.

Journal title

Journal of Biological Chemistry

Volume

292

Issue

35

Pagination

14425-14437

Language

English

RIS ID

116253

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