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Peptidylarginine Deiminases and Protein Deimination in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 52496

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Prof. Dr. Sigrun Lange

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Guest Editor

Tissue Architecture and Regeneration Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
Interests: peptidylarginine deiminases; extracellular vesicles; regenerative medicine; central nervous system; stem cells; mucosal immunity; innate immunity; complement system; host-pathogen interactions; comparative immunology; autoimmunity; chronic inflammation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Anthony P Nicholas

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University of Alabama at Birmingham, Birmingham, AL, USA
Interests: Parkinson's disease; protein deimination (citrullination); levodopa-induced dyskinesia; cervical dystonia

Special Issue Information

Dear Colleagues,

Peptidylarginine deiminases (PADs) are a group of calcium-dependent enzymes that are conserved throughout phylogeny and involved in physiological and pathophysiological processes. PADs cause post-translational deimination of proteins by converting arginine into citrulline (citrullination/deimination), resulting in structural and functional changes in target proteins.
The field of PADs has grown increasingly in the past few years with PADs and post-translational deimination being widely studied in autoimmune and neurodegenerative pathologies as well as in cancer. Protein deimination has, for example, been found to be involved in neo-epitope generation in autoimmunity, as well as neurodegeneration and inflammation, in epigenetic regulation via histone deimination in cancers and in the regulation of extracellular vesicle release.
The development of PAD inhibitors and PAD-knockout models has helped in elucidating some PAD-mediated roles in various pathologies. Protective roles for pharmacological PAD inhibitors have for example been shown in several animal models of autoimmunity and acute CNS injury, while regulatory roles for PAD inhibitors on histone modifications and extracellular vesicle release have been implicated in cancers, including sensitisation to chemotherapy.
While the physiological roles of PADs have been less studied, implications have been found in CNS development, embryo-preimplantation and in mucosal and innate immunity, among others. Post-translational protein changes, such as protein deimination, may facilitate protein moonlighting, an evolutionary acquired phenomenon where proteins are allowed to exhibit more than one physiologically relevant function within one polypeptide chain.
This Special Issue aims to collect state-of-the-art primary research studies and review articles from international experts and diverse leading groups in the field to update our current understanding of the contributions of PADs in both physiological and pathophysiological processes.

Dr. Sigrun Lange
Prof. Dr. Anthony P Nicholas
Guest Editors

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Keywords

Peptidylargine deiminases
Posttranslational protein deimination
Autoimmunity
CNS injury
Neurodegeneration
Inflammation
Cancer
Epigenetics
Immunity
Reproduction
PAD antagonists
PAD animal models

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Research

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21 pages, 3468 KiB

Open AccessArticle

Controlled Delivery of Pan-PAD-Inhibitor Cl-Amidine Using Poly(3-Hydroxybutyrate) Microspheres

by Dina Ahmed, Hima Puthussery, Pooja Basnett, Jonathan C. Knowles, Sigrun Lange and Ipsita Roy

Int. J. Mol. Sci. 2021, 22(23), 12852; https://doi.org/10.3390/ijms222312852 - 27 Nov 2021

Cited by 6 | Viewed by 3375

Abstract

This study deals with the process of optimization and synthesis of Poly(3-hydroxybutyrate) microspheres with encapsulated Cl-amidine. Cl-amidine is an inhibitor of peptidylarginine deiminases (PADs), a group of calcium-dependent enzymes, which play critical roles in a number of pathologies, including autoimmune and neurodegenerative diseases, as well as cancer. While Cl-amidine application has been assessed in a number of in vitro and in vivo models; methods of controlled release delivery remain to be investigated. P(3HB) microspheres have proven to be an effective delivery system for several compounds applied in antimicrobial, wound healing, cancer, and cardiovascular and regenerative disease models. In the current study, P(3HB) microspheres with encapsulated Cl-amidine were produced in a size ranging from ~4–5 µm and characterized for surface morphology, porosity, hydrophobicity and protein adsorption, in comparison with empty P(3HB) microspheres. Cl-amidine encapsulation in P(3HB) microspheres was optimized, and these were found to be less hydrophobic, compared with the empty microspheres, and subsequently adsorbed a lower amount of protein on their surface. The release kinetics of Cl-amidine from the microspheres were assessed in vitro and expressed as a function of encapsulation efficiency. There was a burst release of ~50% Cl-amidine in the first 24 h and a zero order release from that point up to 16 days, at which time point ~93% of the drug had been released. As Cl-amidine has been associated with anti-cancer effects, the Cl-amidine encapsulated microspheres were assessed for the inhibition of vascular endothelial growth factor (VEGF) expression in the mammalian breast cancer cell line SK-BR-3, including in the presence of the anti-proliferative drug rapamycin. The cytotoxicity of the combinatorial effect of rapamycin with Cl-amidine encapsulated P(3HB) microspheres was found to be 3.5% more effective within a 24 h period. The cells treated with Cl-amidine encapsulated microspheres alone, were found to have 36.5% reduction in VEGF expression when compared with untreated SK-BR-3 cells. This indicates that controlled release of Cl-amidine from P(3HB) microspheres may be effective in anti-cancer treatment, including in synergy with chemotherapeutic agents. Using controlled drug-delivery of Cl-amidine encapsulated in Poly(3-hydroxybutyrate) microspheres may be a promising novel strategy for application in PAD-associated pathologies. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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30 pages, 7430 KiB

Open AccessArticle

Putative Roles for Peptidylarginine Deiminases in COVID-19

by Elif Damla Arisan, Pinar Uysal-Onganer and Sigrun Lange

Int. J. Mol. Sci. 2020, 21(13), 4662; https://doi.org/10.3390/ijms21134662 - 30 Jun 2020

Cited by 28 | Viewed by 5872

Abstract

Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients’ tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1–6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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17 pages, 1799 KiB

Open AccessArticle

Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome

by Guangyuan Li, Coleman H. Young, Bryce Snow, Amanda O. Christensen, M. Kristen Demoruelle, Venkatesh V. Nemmara, Paul R. Thompson, Heather M. Rothfuss and Brian D. Cherrington

Int. J. Mol. Sci. 2020, 21(7), 2634; https://doi.org/10.3390/ijms21072634 - 10 Apr 2020

Cited by 6 | Viewed by 3531

Abstract

Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by peptidylarginine deiminase (PAD or PADI) enzymes. The full protein citrullinome in many tissues is unknown. Herein, we used mass spectrometry and identified 107 citrullinated proteins in the lactation day 9 (L9) mouse mammary gland including histone H2A, α-tubulin, and β-casein. Given the importance of prolactin to lactation, we next tested if it stimulates PAD-catalyzed citrullination using mouse mammary epithelial CID-9 cells. Stimulation of CID-9 cells with 5 µg/mL prolactin for 10 min induced a 2-fold increase in histone H2A citrullination and a 4.5-fold increase in α-tubulin citrullination. We next investigated if prolactin-induced citrullination regulates the expression of lactation genes β-casein (Csn2) and butyrophilin (Btn1a1). Prolactin treatment for 12 h increased β-casein and butyrophilin mRNA expression; however, this increase was significantly inhibited by the pan-PAD inhibitor, BB-Cl-amidine (BB-ClA). We also examined the effect of tubulin citrullination on the overall polymerization rate of microtubules. Our results show that citrullinated tubulin had a higher maximum overall polymerization rate. Our work suggests that protein citrullination is an important PTM that regulates gene expression and microtubule dynamics in mammary epithelial cells. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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22 pages, 4326 KiB

Open AccessArticle

Peptidylarginine Deiminase of Porphyromonas gingivalis Modulates the Interactions between Candida albicans Biofilm and Human Plasminogen and High-Molecular-Mass Kininogen

by Justyna Karkowska-Kuleta, Magdalena Surowiec, Mariusz Gogol, Joanna Koziel, Barbara Potempa, Jan Potempa, Andrzej Kozik and Maria Rapala-Kozik

Int. J. Mol. Sci. 2020, 21(7), 2495; https://doi.org/10.3390/ijms21072495 - 3 Apr 2020

Cited by 11 | Viewed by 3594

Abstract

Microorganisms that create mixed-species biofilms in the human oral cavity include, among others, the opportunistic fungus Candida albicans and the key bacterial pathogen in periodontitis, Porphyromonas gingivalis. Both species use arsenals of virulence factors to invade the host organism and evade its immune system including peptidylarginine deiminase that citrullinates microbial and host proteins, altering their function. We assessed the effects of this modification on the interactions between the C. albicans cell surface and human plasminogen and kininogen, key components of plasma proteolytic cascades related to the maintenance of hemostasis and innate immunity. Mass spectrometry was used to identify protein citrullination, and microplate tests to quantify the binding of modified plasminogen and kininogen to C. albicans cells. Competitive radioreceptor assays tested the affinity of citrullinated kinins to their specific cellular receptors. The citrullination of surface-exposed fungal proteins reduced the level of unmodified plasminogen binding but did not affect unmodified kininogen binding. However, the modification of human proteins did not disrupt their adsorption to the unmodified fungal cells. In contrast, the citrullination of kinins exerted a significant impact on their interactions with cellular receptors reducing their affinity and thus affecting the role of kinin peptides in the development of inflammation. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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29 pages, 4246 KiB

Open AccessArticle

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

by Pinar Uysal-Onganer, Amy MacLatchy, Rayan Mahmoud, Igor Kraev, Paul R. Thompson, Jameel M. Inal and Sigrun Lange

Int. J. Mol. Sci. 2020, 21(4), 1495; https://doi.org/10.3390/ijms21041495 - 22 Feb 2020

Cited by 39 | Viewed by 6531

Abstract

Glioblastoma multiforme (GBM) is an aggressive adult brain tumour with poor prognosis. Roles for peptidylarginine deiminases (PADs) in GBM have recently been highlighted. Here, two GBM cell lines were treated with PAD2, PAD3 and PAD4 isozyme-specific inhibitors. Effects were assessed on extracellular vesicle (EV) signatures, including EV-microRNA cargo (miR21, miR126 and miR210), and on changes in cellular protein expression relevant for mitochondrial housekeeping (prohibitin (PHB)) and cancer progression (stromal interaction molecule 1 (STIM-1) and moesin), as well as assessing cell invasion. Overall, GBM cell-line specific differences for the three PAD isozyme-specific inhibitors were observed on modulation of EV-signatures, PHB, STIM-1 and moesin protein levels, as well as on cell invasion. The PAD3 inhibitor was most effective in modulating EVs to anti-oncogenic signatures (reduced miR21 and miR210, and elevated miR126), to reduce cell invasion and to modulate protein expression of pro-GBM proteins in LN229 cells, while the PAD2 and PAD4 inhibitors were more effective in LN18 cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for deiminated proteins relating to cancer, metabolism and inflammation differed between the two GBM cell lines. Our findings highlight roles for the different PAD isozymes in the heterogeneity of GBM tumours and the potential for tailored PAD-isozyme specific treatment. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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20 pages, 3761 KiB

Open AccessArticle

Post-Translational Deimination of Immunological and Metabolic Protein Markers in Plasma and Extracellular Vesicles of Naked Mole-Rat (Heterocephalus glaber)

by Matthew E. Pamenter, Pinar Uysal-Onganer, Kenny W. Huynh, Igor Kraev and Sigrun Lange

Int. J. Mol. Sci. 2019, 20(21), 5378; https://doi.org/10.3390/ijms20215378 - 29 Oct 2019

Cited by 25 | Viewed by 4669

Abstract

Naked mole-rats are long-lived animals that show unusual resistance to hypoxia, cancer and ageing. Protein deimination is an irreversible post-translational modification caused by the peptidylarginine deiminase (PAD) family of enzymes, which convert arginine into citrulline in target proteins. Protein deimination can cause structural and functional protein changes, facilitating protein moonlighting, but also leading to neo-epitope generation and effects on gene regulation. Furthermore, PADs have been found to regulate cellular release of extracellular vesicles (EVs), which are lipid-vesicles released from cells as part of cellular communication. EVs carry protein and genetic cargo and are indicative biomarkers that can be isolated from most body fluids. This study was aimed at profiling deiminated proteins in plasma and EVs of naked mole-rat. Key immune and metabolic proteins were identified to be post-translationally deiminated, with 65 proteins specific for plasma, while 42 proteins were identified to be deiminated in EVs only. Using protein-protein interaction network analysis, deiminated plasma proteins were found to belong to KEEG (Kyoto Encyclopedia of Genes and Genomes) pathways of immunity, infection, cholesterol and drug metabolism, while deiminated proteins in EVs were also linked to KEEG pathways of HIF-1 signalling and glycolysis. The mole-rat EV profiles showed a poly-dispersed population of 50–300 nm, similar to observations of human plasma. Furthermore, the EVs were assessed for three key microRNAs involved in cancer, inflammation and hypoxia. The identification of post-translational deimination of critical immunological and metabolic markers contributes to the current understanding of protein moonlighting functions, via post-translational changes, in the longevity and cancer resistance of naked mole-rats. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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20 pages, 3152 KiB

Open AccessArticle

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes

by Valerie R. Wiersma, Alex Clarke, Simon D. Pouwels, Elizabeth Perry, Trefa M. Abdullah, Clive Kelly, Anthony De Soyza, David Hutchinson, Paul Eggleton and Edwin Bremer

Int. J. Mol. Sci. 2019, 20(16), 4046; https://doi.org/10.3390/ijms20164046 - 19 Aug 2019

Cited by 27 | Viewed by 5676

Abstract

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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14 pages, 3272 KiB

Open AccessArticle

Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans

by Aisha M. Mergaert, Mandar Bawadekar, Thai Q. Nguyen, Laura Massarenti, Caitlyn L. Holmes, Ryan Rebernick, Steven J. Schrodi and Miriam A. Shelef

Int. J. Mol. Sci. 2019, 20(12), 3093; https://doi.org/10.3390/ijms20123093 - 25 Jun 2019

Cited by 14 | Viewed by 4395

Abstract

Autoantibodies against citrullinated proteins are a hallmark of rheumatoid arthritis, a destructive inflammatory arthritis. Peptidylarginine deiminase 4 (PAD4) has been hypothesized to contribute to rheumatoid arthritis by citrullinating histones to induce neutrophil extracellular traps (NETs), which display citrullinated proteins that are targeted by autoantibodies to drive inflammation and arthritis. Consistent with this theory, PAD4-deficient mice have reduced NETs, autoantibodies, and arthritis. However, PAD4′s role in human rheumatoid arthritis is less clear. Here, we determine if single nucleotide polymorphism rs2240335 in PADI4, whose G allele is associated with reduced PAD4 in neutrophils, correlates with NETs, anti-histone antibodies, and rheumatoid arthritis susceptibility in North Americans. Control and rheumatoid arthritis subjects, divided into anti-cyclic citrullinated peptide (CCP) antibody positive and negative groups, were genotyped at rs2240335. In homozygotes, in vitro NETosis was quantified in immunofluorescent images and circulating NET and anti-histone antibody levels by enzyme linked immunosorbent assay (ELISA). Results were compared by t-test and correlation of rheumatoid arthritis diagnosis with rs2240335 by Armitage trend test. NET levels did not significantly correlate with genotype. G allele homozygotes in the CCP⁻ rheumatoid arthritis group had reduced anti-native and anti-citrullinated histone antibodies. However, the G allele conferred increased risk for rheumatoid arthritis diagnosis, suggesting a complex role for PAD4 in human rheumatoid arthritis. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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Review

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16 pages, 1514 KiB

Open AccessReview

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

by Miguel Beato and Priyanka Sharma

Int. J. Mol. Sci. 2020, 21(4), 1351; https://doi.org/10.3390/ijms21041351 - 17 Feb 2020

Cited by 42 | Viewed by 6937

Abstract

Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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15 pages, 3243 KiB

Open AccessReview

Deimination and Peptidylarginine Deiminases in Skin Physiology and Diseases

by Marie-Claire Méchin, Hidenari Takahara and Michel Simon

Int. J. Mol. Sci. 2020, 21(2), 566; https://doi.org/10.3390/ijms21020566 - 15 Jan 2020

Cited by 44 | Viewed by 5996

Abstract

Deimination, also known as citrullination, corresponds to the conversion of the amino acid arginine, within a peptide sequence, into the non-standard amino acid citrulline. This post-translational modification is catalyzed by a family of calcium-dependent enzymes called peptidylarginine deiminases (PADs). Deimination is implicated in a growing number of physiological processes (innate and adaptive immunity, gene regulation, embryonic development, etc.) and concerns several human diseases (rheumatoid arthritis, neurodegenerative diseases, female infertility, cancer, etc.). Here, we update the involvement of PADs in both the homeostasis of skin and skin diseases. We particularly focus on keratinocyte differentiation and the epidermal barrier function, and on hair follicles. Indeed, alteration of PAD activity in the hair shaft is responsible for two hair disorders, the uncombable hair syndrome and a particular form of inflammatory scarring alopecia, mainly affecting women of African ancestry. Full article

(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)

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