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

Alexandre Chlenski, Lisa J. Guerrero, Helen R. Salwen, Qiwei Yang, Yufeng Tian, Andres la Madrid, Salida Mirzoeva, Patrice G. Bouyer, David Xu, Matthew Walker, Susan L. Cohn

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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-dimentional 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.

Original languageEnglish (US)
Article numbere23880
JournalPloS one
Volume6
Issue number9
DOIs
StatePublished - Sep 16 2011

Fingerprint

Cysteine
cysteine
extracellular matrix
Extracellular Matrix
Proteins
proteins
Collagen
collagen
Extracellular Matrix Proteins
Fibroblasts
fibroblasts
Degradation
degradation
Tissue
Vitronectin
cells
Physiology
Laminin
Fibronectins
Cell culture

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chlenski, A., Guerrero, L. J., Salwen, H. R., Yang, Q., Tian, Y., la Madrid, A., ... Cohn, S. L. (2011). Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone. PloS one, 6(9), [e23880]. https://doi.org/10.1371/journal.pone.0023880

Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone. / Chlenski, Alexandre; Guerrero, Lisa J.; Salwen, Helen R.; Yang, Qiwei; Tian, Yufeng; la Madrid, Andres; Mirzoeva, Salida; Bouyer, Patrice G.; Xu, David; Walker, Matthew; Cohn, Susan L.

In: PloS one, Vol. 6, No. 9, e23880, 16.09.2011.

Research output: Contribution to journalArticle

Chlenski, A, Guerrero, LJ, Salwen, HR, Yang, Q, Tian, Y, la Madrid, A, Mirzoeva, S, Bouyer, PG, Xu, D, Walker, M & Cohn, SL 2011, 'Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone', PloS one, vol. 6, no. 9, e23880. https://doi.org/10.1371/journal.pone.0023880
Chlenski A, Guerrero LJ, Salwen HR, Yang Q, Tian Y, la Madrid A et al. Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone. PloS one. 2011 Sep 16;6(9). e23880. https://doi.org/10.1371/journal.pone.0023880
Chlenski, Alexandre ; Guerrero, Lisa J. ; Salwen, Helen R. ; Yang, Qiwei ; Tian, Yufeng ; la Madrid, Andres ; Mirzoeva, Salida ; Bouyer, Patrice G. ; Xu, David ; Walker, Matthew ; Cohn, Susan L. / Secreted protein acidic and rich in cysteine is a matrix scavenger chaperone. In: PloS one. 2011 ; Vol. 6, No. 9.
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