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      Cyclophilin B control of lysine post-translational modifications of skin type I collagen

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          Abstract

          Covalent intermolecular cross-linking of collagen is essential for tissue stability. Recent studies have demonstrated that cyclophilin B (CypB), an endoplasmic reticulum (ER)-resident peptidyl-prolyl cis-trans isomerase, modulates lysine (Lys) hydroxylation of type I collagen impacting cross-linking chemistry. However, the extent of modulation, the molecular mechanism and the functional outcome in tissues are not well understood. Here, we report that, in CypB null (KO) mouse skin, two unusual collagen cross-links lacking Lys hydroxylation are formed while neither was detected in wild type (WT) or heterozygous (Het) mice. Mass spectrometric analysis of type I collagen showed that none of the telopeptidyl Lys was hydroxylated in KO or WT/Het mice. Hydroxylation of the helical cross-linking Lys residues was almost complete in WT/Het but was markedly diminished in KO. Lys hydroxylation at other sites was also lower in KO but to a lesser extent. A key glycosylation site, α1(I) Lys-87, was underglycosylated while other sites were mostly overglycosylated in KO. Despite these findings, lysyl hydroxylases and glycosyltransferase 25 domain 1 levels were significantly higher in KO than WT/Het. However, the components of ER chaperone complex that positively or negatively regulates lysyl hydroxylase activities were severely reduced or slightly increased, respectively, in KO. The atomic force microscopy-based nanoindentation modulus were significantly lower in KO skin than WT. These data demonstrate that CypB deficiency profoundly affects Lys post-translational modifications of collagen likely by modulating LH chaperone complexes. Together, our study underscores the critical role of CypB in Lys modifications of collagen, cross-linking and mechanical properties of skin.

          Author summary

          Deficiency of cyclophilin B (CypB), an endoplasmic reticulum-resident peptidyl-prolyl cis-trans isomerase, causes recessive osteogenesis imperfecta type IX, resulting in defective connective tissues. Recent studies using CypB null mice revealed that CypB modulates lysine hydroxylation of type I collagen impacting collagen cross-linking. However, the extent of modulation, the molecular mechanism and the effect on tissue properties are not well understood. In the present study, we show that CypB deficiency in mouse skin results in the formation of unusual collagen cross-links, aberrant tissue formation, altered levels of lysine modifying enzymes and their chaperones, and impaired mechanical property. These findings highlight an essential role of CypB in collagen post-translational modifications which are critical in maintaining the structure and function of connective tissues.

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          Lysine post-translational modifications of collagen.

          Type I collagen is the most abundant structural protein in vertebrates. It is a heterotrimeric molecule composed of two α1 chains and one α2 chain, forming a long uninterrupted triple helical structure with short non-triple helical telopeptides at both the N- and C-termini. During biosynthesis, collagen acquires a number of post-translational modifications, including lysine modifications, that are critical to the structure and biological functions of this protein. Lysine modifications of collagen are highly complicated sequential processes catalysed by several groups of enzymes leading to the final step of biosynthesis, covalent intermolecular cross-linking. In the cell, specific lysine residues are hydroxylated to form hydroxylysine. Then specific hydroxylysine residues located in the helical domain of the molecule are glycosylated by the addition of galactose or glucose-galactose. Outside the cell, lysine and hydroxylysine residues in the N- and C-telopeptides can be oxidatively deaminated to produce reactive aldehydes that undergo a series of non-enzymatic condensation reactions to form covalent intra- and inter-molecular cross-links. Owing to the recent advances in molecular and cellular biology, and analytical technologies, the biological significance and molecular mechanisms of these modifications have been gradually elucidated. This chapter provides an overview on these enzymatic lysine modifications and subsequent cross-linking.
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            The fibrotic tumor stroma.

            Intratumoral fibrosis results from the deposition of a cross-linked collagen matrix by cancer-associated fibroblasts (CAFs). This type of fibrosis has been shown to exert mechanical forces and create a biochemical milieu that, together, shape intratumoral immunity and influence tumor cell metastatic behavior. In this Review, we present recent evidence that CAFs and tumor cells are regulated by provisional matrix molecules, that metastasis results from a change in the type of stromal collagen cross-link, and that fibrosis and inflammation perpetuate each other through proteolytic and chemotactic mediators released into the tumor stroma. We also discuss aspects of the emerging biology that have potential therapeutic value.
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              Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis.

              The hallmark of fibrotic processes is an excessive accumulation of collagen. The deposited collagen shows an increase in pyridinoline cross-links, which are derived from hydroxylated lysine residues within the telopeptides. This change in cross-linking is related to irreversible accumulation of collagen in fibrotic tissues. The increase in pyridinoline cross-links is likely to be the result of increased activity of the enzyme responsible for the hydroxylation of the telopeptides (telopeptide lysyl hydroxylase, or TLH). Although the existence of TLH has been postulated, the gene encoding TLH has not been identified. By analyzing the genetic defect of Bruck syndrome, which is characterized by a pyridinoline deficiency in bone collagen, we found two missense mutations in exon 17 of PLOD2, thereby identifying PLOD2 as a putative TLH gene. Subsequently, we investigated fibroblasts derived from fibrotic skin of systemic sclerosis (SSc) patients and found that PLOD2 mRNA is highly increased indeed. Furthermore, increased pyridinoline cross-link levels were found in the matrix deposited by SSc fibroblasts, demonstrating a clear link between mRNA levels of the putative TLH gene (PLOD2) and the hydroxylation of lysine residues within the telopeptides. These data underscore the significance of PLOD2 in fibrotic processes.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – original draft
                Role: Resources
                Role: Data curation
                Role: Visualization
                Role: SoftwareRole: Visualization
                Role: SoftwareRole: Visualization
                Role: Data curationRole: Software
                Role: Software
                Role: Funding acquisitionRole: SoftwareRole: Validation
                Role: Data curation
                Role: Software
                Role: Resources
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                7 June 2019
                June 2019
                : 15
                : 6
                : e1008196
                Affiliations
                [1 ] Oral and Craniofacial Health Sciences, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [2 ] Nippi Research Institute of Biomatrix, Toride, Ibaraki, Japan
                [3 ] Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, National Institutes of Health, Bethesda, Maryland, United States of America
                [4 ] Molecular Genetics Section, Medical Genomics and Metabolic Genetics Branch, NHGRI, National Institutes of Health, Bethesda, Maryland, United States of America
                [5 ] Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
                [6 ] Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America
                [7 ] School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania, United States of America
                [8 ] Fujifilm Diosynth Biotechnologies, Morrisville, North Carolina, United States of America
                Stanford University School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1502-7930
                http://orcid.org/0000-0001-9100-758X
                http://orcid.org/0000-0002-0563-5289
                Article
                PGENETICS-D-19-00047
                10.1371/journal.pgen.1008196
                6602281
                31173582
                60b7555d-9df1-4124-a3f3-55b701534005

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 31 January 2019
                : 14 May 2019
                Page count
                Figures: 5, Tables: 4, Pages: 26
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: R21AR060978
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: 49277
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: 42630
                Award Recipient :
                This study was supported in part by NIH-NIAMS R21AR060978 (MY) and NIH-NHLBI49277/NHLBI42630 (NM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Collagens
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Hydroxylation
                Physical Sciences
                Chemistry
                Physical Chemistry
                Chemical Bonding
                Cross-Linking
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycosylation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Glycosylation
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Pepsins
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Pepsins
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Hydrolases
                Pepsins
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Hydrolases
                Pepsins
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Tendons
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Tendons
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-07-01
                All relevant data are within the manuscript and its Supporting Information files.

                Genetics
                Genetics

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