Calcium Regulation of Bacterial Virulence

King, Michelle M.; Kayastha, Biraj B.; Franklin, Michael J.; Patrauchan, Marianna A.

doi:10.1007/978-3-030-12457-1_33

Cited by 43 publications

(33 citation statements)

References 227 publications

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“…KEGG pathways for calcium signalling pathway were here identified to be enriched in deiminated proteins in whole bovine serum only. Calcium is a key modulator in a range of immunological, metabolic and developmental functions [199][200][201][202]. Calcium signalling is linked to a wide range of physiological and pathological processes [203][204][205], is a key driver for post-translational deimination [206][207][208] and plays an important role in the regulation of EVs [11,48].…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Criscitiello

Kraev

Lange

2020

IJMS

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The bovine immune system is known for its unusual traits relating to immunoglobulin and antiviral responses. Peptidylarginine deiminases (PADs) are phylogenetically conserved enzymes that cause post-translational deimination, contributing to protein moonlighting in health and disease. PADs also regulate extracellular vesicle (EV) release, forming a critical part of cellular communication. As PAD-mediated mechanisms in bovine immunology and physiology remain to be investigated, this study profiled deimination signatures in serum and serum-EVs in Bos taurus. Bos EVs were poly-dispersed in a 70-500 nm size range and showed differences in deiminated protein cargo, compared with whole sera. Key immune, metabolic and gene regulatory proteins were identified to be post-translationally deiminated with some overlapping hits in sera and EVs (e.g., immunoglobulins), while some were unique to either serum or serum-EVs (e.g., histones). Protein-protein interaction network analysis of deiminated proteins revealed KEGG pathways common for serum and serum-EVs, including complement and coagulation cascades, viral infection (enveloped viruses), viral myocarditis, bacterial and parasitic infections, autoimmune disease, immunodeficiency intestinal IgA production, B-cell receptor signalling, natural killer cell mediated cytotoxicity, platelet activation and hematopoiesis, alongside metabolic pathways including ferroptosis, vitamin digestion and absorption, cholesterol metabolism and mineral absorption. KEGG pathways specific to EVs related to HIF-1 signalling, oestrogen signalling and biosynthesis of amino acids. KEGG pathways specific for serum only, related to Epstein-Barr virus infection, transcription mis-regulation in cancer, bladder cancer, Rap1 signalling pathway, calcium signalling pathway and ECM-receptor interaction. This indicates differences in physiological and pathological pathways for deiminated proteins in serum-EVs, compared with serum. Our findings may shed light on pathways underlying a number of pathological and anti-pathogenic (viral, bacterial, parasitic) pathways, with putative translatable value to human pathologies, zoonotic diseases and development of therapies for infections, including anti-viral therapies.

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Section: Discussionmentioning

confidence: 99%

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Criscitiello

Kraev

Lange

2020

IJMS

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“…GO biological and molecular pathways identified in the deiminated Limulus proteins related to a range of immune and metabolic functions, as well as to developmental processes, and this correlates to multifaceted functions of these deiminated protein candidates identified in immunity and development, highlighting their moonlighting abilities. PFAM protein domains identified in the protein networks for deiminated proteins in Limulus also highlighted immune functions in particular, as did the UniProt Keywords, which also emphasised metabolic proteins and highlighted calcium, which is a key driver of deimination (Alghamdi et al, 2019) and a key modulator in a range of immunological, metabolic and developmental functions (Paupe and Prudent, 2018;King et al, 2020;Puri et al, 2020). A similar relation to immunity and metabolism was seen for the SMART protein domains, INTERPRO protein domains, as well as for the reactome pathways, for the deiminated proteins identified in Limulus in the current study.…”

Section: Limulusmentioning

confidence: 96%

Post-translational protein deimination signatures and extracellular vesicles (EVs) in the Atlantic horseshoe crab (Limulus polyphemus)

Bowden

Kraev

Lange

2020

Developmental & Comparative Immunology

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The horseshoe crab is a living fossil and a species of marine arthropod with unusual immune system properties which are also exploited commercially. Given its ancient status dating to the Ordovician period (450 million years ago), its standing in phylogeny and unusual immunological characteristics, the horseshoe crab may hold valuable information for comparative immunology studies.Peptidylarginine deiminases (PADs) are calcium dependent enzymes that are phylogenetically conserved and cause protein deimination via conversion of arginine to citrulline. This posttranslational modification can lead to structural and functional protein changes contributing to protein moonlighting in health and disease. PAD-mediated regulation of extracellular vesicle (EV) release, a critical component of cellular communication, has furthermore been identified to be a phylogenetically conserved mechanism. PADs, protein deimination and EVs have hitherto not been studied in the horseshoe crab and were assessed in the current study. Horseshoe crab haemolymph serum-EVs were found to be a poly-dispersed population in the 20-400 nm size range, with the majority of EVs falling within 40-123 nm. Key immune proteins were identified to be posttranslationally deiminated in horseshoe crab haemolymph serum, providing insights into protein moonlighting function of Limulus and phylogenetically conserved immune proteins. KEGG (Kyoto encyclopaedia of genes and genomes) and GO (gene ontology) enrichment analysis of deiminated proteins identified in Limulus revealed KEGG pathways relating to complement and coagulation pathways, Staphylococcus aureus infection, glycolysis/gluconeogenesis and carbon metabolism, while GO pathways of biological and molecular pathways related to a range of immune and metabolic functions, as well as developmental processes. The characterisation of EVs, and posttranslational deimination signatures, revealed here in horseshoe crab, contributes to current understanding of protein moonlighting functions and EV-mediated communication in this ancient arthropod and throughout phylogeny.

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“…In contrast to eukaryotes where the molecular mechanisms for changes in [Ca 2+ ]i are well understood, in prokaryotes much work needs to be done. However, there is growing evidence that Ca 2+ also plays a regulatory role in prokaryotes (Broder et al, 2016;Fishman et al, 2018;Moretti et al, 2019;King et al, 2020). Ca 2+ ions are involved in numerous bacterial cellular processes including: chemotaxis, transport mechanisms, cell differentiation, virulence, gene expression and others (Fishman et al, 2018;Moretti et al, 2019;Takahashi and Kopriva, 2019; for reviews see Domínguez, 2004;Domínguez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Bacteria respond to environmental stimuli (oxidative stress, cold and heat, changes in pH, salinity and osmotic stress including antimicrobials) by changes in intracellular calcium ion, [Ca 2+ ]i, (Knight et al, 1991;Herbaud et al, 1998;Torrecilla et al, 2000Torrecilla et al, , 2001Naseem et al, 2009;González-Pleiter et al, 2017). Since changes in [Ca 2+ ]i are linked to gene expression (Naseem et al, 2009;Domínguez et al, 2011) and virulence (Sarkisova et al, 2005;Broder et al, 2016;Moretti et al, 2019;King et al, 2020), we hypothesize that when S. aureus cells are exposed to antibiotics or other drugs, they respond by spiking [Ca 2+ ]i, which in turn stimulates efflux pump activity. We tested this hypothesis on one of the multi-drug resistant pump proteins of S. aureus, the LmrS, by looking at changes in activity of excretion of EtBr from cells upon varying intracellular Ca 2+ concentrations and by measuring whether the addition of antibiotics to S. aureus cells could increase their [Ca 2+ ]i concentrations.…”

Section: Introductionmentioning

confidence: 99%

Evidence of Calcium Signaling and Modulation of the LmrS Multidrug Resistant Efflux Pump Activity by Ca2 + Ions in S. aureus

et al. 2020

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Calcium ions (Ca 2+) play a pivotal role in eukaryote cell signaling and regulate many physiological functions. Although a similar role for Ca 2+ in prokaryotes has been difficult to demonstrate, there is increasing evidence for Ca 2+ as a cell regulator in bacteria. The purpose of this study was to investigate Ca 2+ signaling and the effect of Ca 2+ on the Staphylococcus aureus multidrug resistant efflux pump LmrS. We hypothesized that antibiotics act by increasing Ca 2+ concentrations, which in turn enhance the efflux activity of LmrS. These Ca 2+ transients were measured by luminometry in response to various antibiotics by using the photoprotein aequorin reconstituted within live bacterial cells. Efflux associated with LmrS was measured by the increase in fluorescence due to the loss of ethidium bromide (EtBr) from both S. aureus cells and from E. coli cells in which the lmrs gene of S. aureus was expressed. We found that addition of antibiotics to cells generated unique cytosolic Ca 2+ transients and that addition of CaCl 2 to cells enhanced EtBr efflux whereas addition of Ca 2+ chelators or efflux pump inhibitors significantly decreased EtBr efflux from cells. We conclude that antibiotics induce a Ca 2+ mediated response through transients in cytosolic Ca 2+ , which then stimulates LmrS efflux pump.

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Calcium Regulation of Bacterial Virulence

Cited by 43 publications

References 227 publications

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

Post-translational protein deimination signatures and extracellular vesicles (EVs) in the Atlantic horseshoe crab (Limulus polyphemus)

Evidence of Calcium Signaling and Modulation of the LmrS Multidrug Resistant Efflux Pump Activity by Ca2 + Ions in S. aureus

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