Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.

Secreted Protein Acidic and Rich in Cysteine (SPARC) is one of the major non-structural proteins of the extracellular matrix (ECM) in remodeling tissues. The functional significance of SPARC is emphasized by its origin in the first multicellular organisms and its high degree of evolutionary conserva...

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Autores principales: Alexandre Chlenski, Lisa J Guerrero, Helen R Salwen, Qiwei Yang, Yufeng Tian, Andres Morales La Madrid, Salida Mirzoeva, Patrice G Bouyer, David Xu, Matthew Walker, Susan L Cohn
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Publicado: Public Library of Science (PLoS) 2011
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Acceso en línea:https://doaj.org/article/41deb373785f44e0a7476c19f9f08abb
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spelling oai:doaj.org-article:41deb373785f44e0a7476c19f9f08abb2021-11-04T06:08:26ZSecreted protein acidic and rich in cysteine is a matrix scavenger chaperone.1932-620310.1371/journal.pone.0023880https://doaj.org/article/41deb373785f44e0a7476c19f9f08abb2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21949685/?tool=EBIhttps://doaj.org/toc/1932-6203Secreted Protein Acidic and Rich in Cysteine (SPARC) is one of the major non-structural proteins of the extracellular matrix (ECM) in remodeling tissues. The functional significance of SPARC is emphasized by its origin in the first multicellular organisms and its high degree of evolutionary conservation. Although SPARC has been shown to act as a critical modulator of ECM remodeling with profound effects on tissue physiology and architecture, no plausible molecular mechanism of its action has been proposed. In the present study, we demonstrate that SPARC mediates the disassembly and degradation of ECM networks by functioning as a matricellular chaperone. While it has low affinity to its targets inside the cells where the Ca(2+) concentrations are low, high extracellular concentrations of Ca(2+) activate binding to multiple ECM proteins, including collagens. We demonstrated that in vitro, this leads to the inhibition of collagen I fibrillogenesis and disassembly of pre-formed collagen I fibrils by SPARC at high Ca(2+) concentrations. In cell culture, exogenous SPARC was internalized by the fibroblast cells in a time- and concentration-dependent manner. Pulse-chase assay further revealed that internalized SPARC is quickly released outside the cell, demonstrating that SPARC shuttles between the cell and ECM. Fluorescently labeled collagen I, fibronectin, vitronectin, and laminin were co-internalized with SPARC by fibroblasts, and semi-quantitative Western blot showed that SPARC mediates internalization of collagen I. Using a novel 3-dimensional model of fluorescent ECM networks pre-deposited by live fibroblasts, we demonstrated that degradation of ECM depends on the chaperone activity of SPARC. These results indicate that SPARC may represent a new class of scavenger chaperones, which mediate ECM degradation, remodeling and repair by disassembling ECM networks and shuttling ECM proteins into the cell. Further understanding of this mechanism may provide insight into the pathogenesis of matrix-associated disorders and lead to the novel treatment strategies.Alexandre ChlenskiLisa J GuerreroHelen R SalwenQiwei YangYufeng TianAndres Morales La MadridSalida MirzoevaPatrice G BouyerDavid XuMatthew WalkerSusan L CohnPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e23880 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Alexandre Chlenski
Lisa J Guerrero
Helen R Salwen
Qiwei Yang
Yufeng Tian
Andres Morales La Madrid
Salida Mirzoeva
Patrice G Bouyer
David Xu
Matthew Walker
Susan L Cohn
Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
description Secreted Protein Acidic and Rich in Cysteine (SPARC) is one of the major non-structural proteins of the extracellular matrix (ECM) in remodeling tissues. The functional significance of SPARC is emphasized by its origin in the first multicellular organisms and its high degree of evolutionary conservation. Although SPARC has been shown to act as a critical modulator of ECM remodeling with profound effects on tissue physiology and architecture, no plausible molecular mechanism of its action has been proposed. In the present study, we demonstrate that SPARC mediates the disassembly and degradation of ECM networks by functioning as a matricellular chaperone. While it has low affinity to its targets inside the cells where the Ca(2+) concentrations are low, high extracellular concentrations of Ca(2+) activate binding to multiple ECM proteins, including collagens. We demonstrated that in vitro, this leads to the inhibition of collagen I fibrillogenesis and disassembly of pre-formed collagen I fibrils by SPARC at high Ca(2+) concentrations. In cell culture, exogenous SPARC was internalized by the fibroblast cells in a time- and concentration-dependent manner. Pulse-chase assay further revealed that internalized SPARC is quickly released outside the cell, demonstrating that SPARC shuttles between the cell and ECM. Fluorescently labeled collagen I, fibronectin, vitronectin, and laminin were co-internalized with SPARC by fibroblasts, and semi-quantitative Western blot showed that SPARC mediates internalization of collagen I. Using a novel 3-dimensional model of fluorescent ECM networks pre-deposited by live fibroblasts, we demonstrated that degradation of ECM depends on the chaperone activity of SPARC. These results indicate that SPARC may represent a new class of scavenger chaperones, which mediate ECM degradation, remodeling and repair by disassembling ECM networks and shuttling ECM proteins into the cell. Further understanding of this mechanism may provide insight into the pathogenesis of matrix-associated disorders and lead to the novel treatment strategies.
format article
author Alexandre Chlenski
Lisa J Guerrero
Helen R Salwen
Qiwei Yang
Yufeng Tian
Andres Morales La Madrid
Salida Mirzoeva
Patrice G Bouyer
David Xu
Matthew Walker
Susan L Cohn
author_facet Alexandre Chlenski
Lisa J Guerrero
Helen R Salwen
Qiwei Yang
Yufeng Tian
Andres Morales La Madrid
Salida Mirzoeva
Patrice G Bouyer
David Xu
Matthew Walker
Susan L Cohn
author_sort Alexandre Chlenski
title Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
title_short Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
title_full Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
title_fullStr Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
title_full_unstemmed Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
title_sort secreted protein acidic and rich in cysteine is a matrix scavenger chaperone.
publisher Public Library of Science (PLoS)
publishDate 2011
url https://doaj.org/article/41deb373785f44e0a7476c19f9f08abb
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