HSP90 as a regulator of extracellular matrix dynamics

Biochemical Society Transactions ◽

10.1042/bst20210374 ◽

2021 ◽

Author(s):

Abir Chakraborty ◽

Adrienne Lesley Edkins

Keyword(s):

Extracellular Matrix ◽

Molecular Chaperone ◽

Prognostic Value ◽

Therapeutic Potential ◽

Tissue Homeostasis ◽

Protein Homeostasis ◽

Matrix Dynamics

The extracellular matrix (ECM) is a dynamic and organised extracellular network assembled from proteins and carbohydrates exported from the cell. The ECM is critical for multicellular life, providing spatial and temporal cellular cues to maintain tissue homeostasis. Consequently, ECM production must be carefully balanced with turnover to ensure homeostasis; ECM dysfunction culminates in disease. Hsp90 is a molecular chaperone central to protein homeostasis, including in the ECM. Intracellular and extracellular Hsp90 isoforms collaborate to regulate the levels and status of proteins in the ECM via multiple mechanisms. In so doing, Hsp90 regulates ECM dynamics, and changes in Hsp90 levels or activity support the development of ECM-related diseases, like cancer and fibrosis. Consequently, Hsp90 levels may have prognostic value, while inhibition of Hsp90 may have therapeutic potential in conditions characterised by ECM dysfunction.

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Clinical relevance of CD70 expression in resected pancreatic cancer: Prognostic value and therapeutic potential

Pancreatology ◽

10.1016/j.pan.2021.01.013 ◽

2021 ◽

Author(s):

Kota Nakamura ◽

Masayuki Sho ◽

Takahiro Akahori ◽

Satoshi Nishiwada ◽

Tomohiro Kunishige ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Relevance ◽

Prognostic Value ◽

Therapeutic Potential

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Therapeutic Potential of the Molecular Chaperone and Matrix Metalloproteinase Inhibitor Clusterin for Dry Eye

International Journal of Molecular Sciences ◽

10.3390/ijms22010116 ◽

2020 ◽

Vol 22 (1) ◽

pp. 116

Author(s):

M. Elizabeth Fini ◽

Shinwu Jeong ◽

Mark R. Wilson

Keyword(s):

Epithelial Cell ◽

Matrix Metalloproteinase ◽

Dry Eye ◽

Molecular Chaperone ◽

Ocular Surface ◽

Therapeutic Potential ◽

Autoimmune Response ◽

Interacting Protein ◽

Bodily Fluids ◽

Epithelial Cell Layer

Evidence is presented herein supporting the potential of the natural homeostatic glycoprotein CLU (clusterin) as a novel therapeutic for the treatment of dry eye. This idea began with the demonstration that matrix metalloproteinase MMP9 is required for damage to the ocular surface in mouse dry eye. Damage was characterized by degradation of OCLN (occludin), a known substrate of MMP9 and a key component of the paracellular barrier. Following up on this finding, a yeast two-hybrid screen was conducted using MMP9 as the bait to identify other proteins involved. CLU emerged as a strong interacting protein that inhibits the enzymatic activity of MMP9. Previously characterized as a molecular chaperone, CLU is expressed prominently by epithelia at fluid-tissue interfaces and secreted into bodily fluids, where it protects cells and tissues against damaging stress. It was demonstrated that CLU also protects the ocular surface in mouse dry eye when applied topically to replace the natural protein depleted from the dysfunctional tears. CLU is similarly depleted from tears in human dry eye. The most novel and interesting finding was that CLU binds selectively to the damaged ocular surface. In this position, CLU protects against epithelial cell death and barrier proteolysis, and dampens the autoimmune response, while the apical epithelial cell layer is renewed. When present at high enough concentration, CLU also blocks staining by vital dyes used clinically to diagnose dry eye. None of the current therapeutics have this combination of properties to “protect, seal, and heal”. Future work will be directed towards human clinical trials to investigate the therapeutic promise of CLU.

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Biofunctional Peptide FNIII14: Therapeutic Potential

Encyclopedia ◽

10.3390/encyclopedia1020029 ◽

2021 ◽

Vol 1 (2) ◽

pp. 350-359

Author(s):

Motomichi Fujita ◽

Manabu Sasada ◽

Takuya Iyoda ◽

Satoshi Osada ◽

Hiroaki Kodama ◽

...

Keyword(s):

Molecular Structure ◽

Extracellular Matrix ◽

Conformational Changes ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Malignant Tumors ◽

Β1 Integrin ◽

Inactive Form ◽

Functional Inactivation ◽

Organ Fibrosis

Biofunctional peptide FNIII14, which is derived from the 14th fibronectin (FN) type III-like (FN-III) repeat of FN molecule, is capable of inhibiting cell adhesion to the extracellular matrix (ECM). This functional site is usually buried within the molecular structure of FN, but can be exposed by conformational changes and proteolytic cleavage. Peptide FNIII14 can induce a conformational change in β1-integrin from the active to the inactive form, causing functional inactivation. Based on this anti-adhesive activity, peptide FNIII14 exhibits therapeutic potential for several diseases such as metabolic diseases, organ fibrosis, and malignant tumors. Peptide FNIII14 blocks integrin-mediated signaling by a mechanism entirely distinct from that of conventional antagonisitic peptides, including Arg-Gly-Asp peptides that competitively inhibit the ECM binding of integrin.

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Concise Review: The Endothelial Cell Extracellular Matrix Regulates Tissue Homeostasis and Repair

Stem Cells Translational Medicine ◽

10.1002/sctm.18-0155 ◽

2018 ◽

Vol 8 (4) ◽

pp. 375-382 ◽

Cited By ~ 13

Author(s):

Franca M. R. Witjas ◽

Bernard M. van den Berg ◽

Cathelijne W. van den Berg ◽

Marten A. Engelse ◽

Ton J. Rabelink

Keyword(s):

Extracellular Matrix ◽

Endothelial Cell ◽

Tissue Homeostasis ◽

Concise Review

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Plasmid-encoded H-NS controls extracellular matrix composition in a modern Acinetobacter baumannii urinary isolate

Journal of Bacteriology ◽

10.1128/jb.00277-21 ◽

2021 ◽

Author(s):

Saida Benomar ◽

Gisela Di Venanzio ◽

Mario F. Feldman

Keyword(s):

Extracellular Matrix ◽

Antibiotic Resistance ◽

Acinetobacter Baumannii ◽

Gene Cluster ◽

Biofilm Formation ◽

Therapeutic Potential ◽

Matrix Composition ◽

Type Vi Secretion System ◽

Gram Negative ◽

Conjugative Plasmids

Acinetobacter baumannii is emerging as a multidrug-resistant (MDR) nosocomial pathogen of increasing threat to human health worldwide. The recent MDR urinary isolate UPAB1 carries the plasmid pAB5, a member of a family of large conjugative plasmids (LCP). LCP encode several antibiotic resistance genes and repress the type VI secretion system (T6SS) to enable their dissemination, employing two TetR transcriptional regulators. Furthermore, pAB5 controls the expression of additional chromosomally encoded genes, impacting UPAB1 virulence. Here we show that a pAB5-encoded H-NS transcriptional regulator represses the synthesis of the exopolysaccharide PNAG and the expression of a previously uncharacterized three-gene cluster that encodes a protein belonging to the CsgG/HfaB family. Members of this protein family are involved in amyloid or polysaccharide formation in other species. Deletion of the CsgG homolog abrogated PNAG production and CUP pili formation, resulting in a subsequent reduction in biofilm formation. Although this gene cluster is widely distributed in Gram-negative bacteria, it remains largely uninvestigated. Our results illustrate the complex cross-talks that take place between plasmids and the chromosomes of their bacterial host, which in this case can contribute to the pathogenesis of Acinetobacter . IMPORTANCE The opportunistic human pathogen Acinetobacter baumannii displays the highest reported rates of multidrug resistance among Gram-negative pathogens. Many A. baumannii strains carry large conjugative plasmids like pAB5. In recent years, we have witnessed an increase in knowledge about the regulatory cross-talks between plasmids and bacterial chromosomes. Here we show that pAB5 controls the composition of the bacterial extracellular matrix, resulting in a drastic reduction in biofilm formation. The association between biofilm formation, virulence, and antibiotic resistance is well-documented. Therefore, understanding the factors involved in the regulation of biofilm formation in Acinetobacter has remarkable therapeutic potential.

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