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Review
. 2023 May 1;324(5):C1179-C1197.
doi: 10.1152/ajpcell.00054.2023. Epub 2023 Mar 13.

Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Josephine C Adams  1
Affiliations
Review

Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Josephine C Adams. Am J Physiol Cell Physiol. .

Abstract

The extracellular matrix (ECM) is central to the physiology of animal tissues, through its multifaceted roles in tissue structure, mechanical properties, and cell interactions, and by its cell-signaling activities that regulate cell phenotype and behavior. The secretion of ECM proteins typically involves multiple transport and processing steps within the endoplasmic reticulum and the subsequent compartments of the secretory pathway. Many ECM proteins are substituted with various posttranslational modifications (PTMs) and there is increasing evidence of how PTM additions are required for ECM protein secretion or functionality within the extracellular milieu. The targeting of PTM-addition steps may thus offer opportunities to manipulate ECM quality or quantity, in vitro or in vivo. This review discusses selected examples of PTMs of ECM proteins for which the PTM has known importance for anterograde trafficking and secretion of the core protein, and/or loss-of-function of the respectively modifying enzyme leads to alterations of ECM structure or function with pathophysiological consequences in humans. Members of the protein disulfide isomerase (PDI) family have central roles in disulfide bond formation and isomerization within the endoplasmic reticulum, and are discussed in relation to emerging knowledge of the roles of certain PDIs in ECM production in the pathophysiological context of breast cancer. Cumulative data suggest the possible applicability of inhibition of PDIA3 activity to modulate ECM composition and functionality within the tumor microenvironment.

Keywords: breast cancer; cell adhesion; extracellular matrix; secretome.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1.
Figure 1.
Posttranslational modifications support stable folding of the TSR domains of thrombospondin-1. The structural model [PDB 7YYK (14)] shows the second (purple) and third (red) TSR domains. Disulfide bonds are in yellow, with cysteines numbered from the N-terminus of the domain. The position of the O-fucose modification that shields a disulfide bond to stabilize the folded domain is indicated in TSR3. Diagram prepared in iCn3D (15) and exported from NCBI. TSR, thrombospondin type 1 domain.
Figure 2.
Figure 2.
Role of proline and lysine hydroxylation PTMs in the maturation and assembly of fibrillar collagen molecules. The schematic presents major steps in the processing of fibrillar collagens, with the prolyl and lysyl hydroxylases and schematized target residues in bold. See text for details. Adapted from Fig. 2B of Ref. , and reproduced under author’s permitted use of Portland Press. ER, endoplasmic reticulum; PTMs, posttranslational modifications.
Figure 3.
Figure 3.
Classical PDIs of mammals. A: schematics of domain architecture, based on the human proteins. Cross-hatched regions indicate short, disordered regions, as identified by InterProScan 92.0 (58). SP = secretory signal peptide. B: protein sequence similarity relationships of the classical PDIs from human (Hs = H. sapiens) and mouse (Mm = M. musculus). Analysis was conducted at phylogeny.fr (93), with alignment of sequences by MUSCLE and tree construction in PhyML at default parameters and with 100 cycles of bootstrapping. The tree was visualized in iTOLv6.6; numbers refer to bootstrap values (94). C: schematic diagram of the redox mechanism of PDI. Oxidation of reactive thiols of the CysXXCys motifs in the a and a′ domains results in an “open” conformation of PDI which undergoes substrate-driven dimerization. Through thiol exchange reactions with the substrate protein, the substrate reaches its final, disulfide-bonded, folded conformation and is released for anterograde trafficking and PDI is returned to the reduced, closed state. PDI, protein disulfide isomerase.
Figure 4.
Figure 4.
Effects of loss of PDIA3 activity on cell adhesion, fibronectin deposition, and functional properties of conditioned medium. A: comparison of effects of PACMA-31 (2.5 µM) or 16F16 (5 µM) or DMSO as solvent control on spreading and F-actin organization in MDA-MB-231 human breast cancer cells. Cells were plated in serum-free media for 2 h, then fixed and stained with FITC-phalloidin. Yellow arrows: lamellipodia; green: stress fibers; and purple: cell protrusions. Boxed areas are shown enlarged in the lower row. Reproduced from Ref. , published by Portland Press, and licensed open access under CC-BY 4.0. B: effect of 16F16 treatment on cell-adhesive properties of MDA-MB-231 conditioned medium (CM). Serum-free CM was prepared over 48 h, filtered, and incubated with newly plated MDA-MB-231 cells. After 4 h, adherent cells were fixed, stained with phalloidin-Atto 565, and cell areas measured in ImageJ. Each datapoint is a single cell, bars show mean, and SD reproduced from Ref. , published by American Physiological Society and licensed open access under CC-BY 4.0. C: lack of fibronectin deposition to ECM by pdia3-null MEF. WT-MEF or pdia3-null MEF were plated for 48 h, ECM isolated as described (141), and fibronectin visualized by indirect immunofluorescence. D: pdia3-null MEF are impaired for cell spreading and focal adhesion assembly in serum-free media. Cells were plated for 2 h, fixed, and costained with TRITC-phalloidin, antibody to vinculin, and DAPI; boxed areas also shown as enlargements. E: spreading and focal adhesion assembly by pdia3-null MEF is stimulated by exposure to CM of WT-MEF. CMs were prepared as in B and incubated with newly plated pdia3-null MEF for 2 h, and cells then fixed and costained with TRITC-phalloidin, antibody to vinculin and DAPI; boxed areas also shown as enlargements. Scale bars = 20 µm. C–E: reproduced from Ref. , published by American Physiological Society and licensed open access under CC-BY 4.0. ECM, extracellular matrix; TRITC, tetramethylrhodamine isothiocyanate; WT-MEF, wild-type mouse embryo fibroblasts.
Figure 5.
Figure 5.
Schematic of breast cancer cell-host cell interactions in the tumor microenvironment and the role of paracrine and autocrine interactions in determining ECM composition and cell phenotypes. “X” indicates how loss of PDIA3 activity in tumor cells would inhibit autocrine and paracrine secretions, potentially leading to renormalization of the TME and decreasing the invasive potential of tumor cells. ECM, extracellular matrix; TME, tumor microenvironment.
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