Galectin-4 antimicrobial activity primarily occurs through its C-terminal domain
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains (CRDs), our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize, but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Molecular & cellular proteomics : MCP - (2024) vom: 13. März, Seite 100747 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jan, Hau-Ming [VerfasserIn] |
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| Anmerkungen: |
Date Revised 15.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.mcpro.2024.100747 |
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NLM369802101 |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains (CRDs), our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize, but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Wu, Shang-Chuen |e verfasserin |4 aut | |
| 700 | 1 | |a Stowell, Carter J |e verfasserin |4 aut | |
| 700 | 1 | |a Vallecillo-Zúniga, Mary L |e verfasserin |4 aut | |
| 700 | 1 | |a Paul, Anu |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Kashyap R |e verfasserin |4 aut | |
| 700 | 1 | |a Muthusamy, Sasikala |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Hsien-Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Ayona, Diyoly |e verfasserin |4 aut | |
| 700 | 1 | |a Jajosky, Ryan Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Varadkar, Samata P |e verfasserin |4 aut | |
| 700 | 1 | |a Nakahara, Hirotomo |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Rita |e verfasserin |4 aut | |
| 700 | 1 | |a Bhave, Devika |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, William J |e verfasserin |4 aut | |
| 700 | 1 | |a Yeung, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Hollenhorst, Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Rakoff-Nahoum, Seth |e verfasserin |4 aut | |
| 700 | 1 | |a Cummings, Richard D |e verfasserin |4 aut | |
| 700 | 1 | |a Arthur, Connie M |e verfasserin |4 aut | |
| 700 | 1 | |a Stowell, Sean R |e verfasserin |4 aut | |
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