Citrullination Alters the Antibacterial and Anti-Inflammatory Functions of the Host Defense Peptide Canine Cathelicidin K9CATH In Vitro
Copyright © 2021 by The American Association of Immunologists, Inc..
K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide. Peptidylarginine deiminases (PAD) convert cationic peptidyl arginine to neutral citrulline. Thus, we hypothesized that citrullination is a biologically relevant modification of the peptide that would reduce the antibacterial and LPS-binding activities of K9CATH. Recombinant PAD2 and PAD4 citrullinated K9CATH to various extents and circular dichroism spectroscopy revealed that both native and citrullinated K9CATH exhibited similar α-helical secondary structures. Notably, citrullination of K9CATH reduced its bactericidal activity, abolished its ability to permeabilize the membrane of Gram-negative bacteria and reduced the hemolytic capacity. Electron microscopy showed that citrullinated K9CATH did not cause any morphological changes of Gram-negative bacteria, whereas the native peptide caused clear alterations of membrane integrity, concordant with a rapid bactericidal effect. Finally, citrullination of K9CATH impaired its capacity to inhibit LPS-mediated release of proinflammatory molecules from mouse and canine macrophages. In conclusion, citrullination attenuates the antibacterial and the LPS-binding properties of K9CATH, demonstrating the importance of a net positive charge for antibacterial lysis of bacteria and LPS-binding effects and suggests that citrullination is a means to regulate cathelicidin activities.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:207 |
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| Enthalten in: |
Journal of immunology (Baltimore, Md. : 1950) - 207(2021), 3 vom: 01. Aug., Seite 974-984 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Al Adwani, Salma [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.08.2021 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.4049/jimmunol.2001374 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM328272914 |
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| 100 | 1 | |a Al Adwani, Salma |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Citrullination Alters the Antibacterial and Anti-Inflammatory Functions of the Host Defense Peptide Canine Cathelicidin K9CATH In Vitro |
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| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 by The American Association of Immunologists, Inc. | ||
| 520 | |a K9CATH is the sole cathelicidin in canines (dogs) and exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. K9CATH also modulates inflammatory responses and binds to LPS. These activities depend on the secondary structure and a net-positive charge of the peptide. Peptidylarginine deiminases (PAD) convert cationic peptidyl arginine to neutral citrulline. Thus, we hypothesized that citrullination is a biologically relevant modification of the peptide that would reduce the antibacterial and LPS-binding activities of K9CATH. Recombinant PAD2 and PAD4 citrullinated K9CATH to various extents and circular dichroism spectroscopy revealed that both native and citrullinated K9CATH exhibited similar α-helical secondary structures. Notably, citrullination of K9CATH reduced its bactericidal activity, abolished its ability to permeabilize the membrane of Gram-negative bacteria and reduced the hemolytic capacity. Electron microscopy showed that citrullinated K9CATH did not cause any morphological changes of Gram-negative bacteria, whereas the native peptide caused clear alterations of membrane integrity, concordant with a rapid bactericidal effect. Finally, citrullination of K9CATH impaired its capacity to inhibit LPS-mediated release of proinflammatory molecules from mouse and canine macrophages. In conclusion, citrullination attenuates the antibacterial and the LPS-binding properties of K9CATH, demonstrating the importance of a net positive charge for antibacterial lysis of bacteria and LPS-binding effects and suggests that citrullination is a means to regulate cathelicidin activities | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Antimicrobial Cationic Peptides |2 NLM | |
| 650 | 7 | |a Inflammation Mediators |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
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| 650 | 7 | |a Cathelicidins |2 NLM | |
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| 700 | 1 | |a Karadottir, Harpa |e verfasserin |4 aut | |
| 700 | 1 | |a Mörman, Cecilia |e verfasserin |4 aut | |
| 700 | 1 | |a Gräslund, Astrid |e verfasserin |4 aut | |
| 700 | 1 | |a Végvári, Ákos |e verfasserin |4 aut | |
| 700 | 1 | |a Johansson, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Rising, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Agerberth, Birgitta |e verfasserin |4 aut | |
| 700 | 1 | |a Bergman, Peter |e verfasserin |4 aut | |
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