EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption
Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/171557 |
| _version_ | 1811680157170139136 |
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| author | Pinilla, Miriam Mazars, Raoul Vergé, Romain Gorse, Leana Paradis, Margaux Suire, Bastien Santoni, Karin Robinson, Kim Samirah Toh, Gee Ann Prouvensier, Laure Leon-Icaza, Stephen Adonai Hessel, Audrey Péricat, David Murris, Marlène Guet-Revillet, Hélène Henras, Anthony Buyck, Julien Ravet, Emmanuel Zhong, Franklin Cougoule, Céline Planès, Rémi Meunier, Etienne |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Pinilla, Miriam Mazars, Raoul Vergé, Romain Gorse, Leana Paradis, Margaux Suire, Bastien Santoni, Karin Robinson, Kim Samirah Toh, Gee Ann Prouvensier, Laure Leon-Icaza, Stephen Adonai Hessel, Audrey Péricat, David Murris, Marlène Guet-Revillet, Hélène Henras, Anthony Buyck, Julien Ravet, Emmanuel Zhong, Franklin Cougoule, Céline Planès, Rémi Meunier, Etienne |
| author_sort | Pinilla, Miriam |
| collection | NTU |
| description | Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxin released by P. aeruginosa type 2 secretion system (T2SS), during chronic infection. Mechanistically, EXOA-driven eukaryotic elongation factor 2 (EEF2) ribosylation and covalent inactivation promote ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, diphtheria toxin and cholix toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress-associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, cystic fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress-dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2. |
| first_indexed | 2024-10-01T03:20:35Z |
| format | Journal Article |
| id | ntu-10356/171557 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:20:35Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1715572023-11-05T15:39:12Z EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption Pinilla, Miriam Mazars, Raoul Vergé, Romain Gorse, Leana Paradis, Margaux Suire, Bastien Santoni, Karin Robinson, Kim Samirah Toh, Gee Ann Prouvensier, Laure Leon-Icaza, Stephen Adonai Hessel, Audrey Péricat, David Murris, Marlène Guet-Revillet, Hélène Henras, Anthony Buyck, Julien Ravet, Emmanuel Zhong, Franklin Cougoule, Céline Planès, Rémi Meunier, Etienne Lee Kong Chian School of Medicine (LKCMedicine) Skin Research Institute of Singapore Science::Medicine Elongation Factor 2 Inflammasome Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxin released by P. aeruginosa type 2 secretion system (T2SS), during chronic infection. Mechanistically, EXOA-driven eukaryotic elongation factor 2 (EEF2) ribosylation and covalent inactivation promote ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, diphtheria toxin and cholix toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress-associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, cystic fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress-dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2. Published version This project was supported by the ATIP-Avenir program (to E. Meunier), Fondation pour la Recherche Médicale “Amorçage Jeunes Equipes” (AJE20151034460 to E. Meunier), the Agence Nationale de la Recherche (ANR Psicopak to E. Meunier), the Agence nationale de recherche sur le sida et les hépatites-Maladies infectieuses émergentes (to E. Meunier), the European Research Council (StG INFLAME 804249 to E. Meunier), the European Society of Clinical Microbiology and Infectious Diseases (to R. Planès), Invivogen-Conventions industrielles de formation par la recherche PhD grant (to M. Pinilla), Vaincre La Mucoviscidose, and Region Occitanie (Groupement de Recherche pour des Applications INnovantes avec les Entreprises) grants to C. Cougoule. 2023-10-31T00:46:58Z 2023-10-31T00:46:58Z 2023 Journal Article Pinilla, M., Mazars, R., Vergé, R., Gorse, L., Paradis, M., Suire, B., Santoni, K., Robinson, K. S., Toh, G. A., Prouvensier, L., Leon-Icaza, S. A., Hessel, A., Péricat, D., Murris, M., Guet-Revillet, H., Henras, A., Buyck, J., Ravet, E., Zhong, F., ...Meunier, E. (2023). EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption. Journal of Experimental Medicine, 220(10), e20230104-. https://dx.doi.org/10.1084/jem.20230104 0022-1007 https://hdl.handle.net/10356/171557 10.1084/jem.20230104 37642996 2-s2.0-85168952681 10 220 e20230104 en Journal of Experimental Medicine © 2023 Pinilla et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Science::Medicine Elongation Factor 2 Inflammasome Pinilla, Miriam Mazars, Raoul Vergé, Romain Gorse, Leana Paradis, Margaux Suire, Bastien Santoni, Karin Robinson, Kim Samirah Toh, Gee Ann Prouvensier, Laure Leon-Icaza, Stephen Adonai Hessel, Audrey Péricat, David Murris, Marlène Guet-Revillet, Hélène Henras, Anthony Buyck, Julien Ravet, Emmanuel Zhong, Franklin Cougoule, Céline Planès, Rémi Meunier, Etienne EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title | EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title_full | EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title_fullStr | EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title_full_unstemmed | EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title_short | EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| title_sort | eef2 inactivating toxins engage the nlrp1 inflammasome and promote epithelial barrier disruption |
| topic | Science::Medicine Elongation Factor 2 Inflammasome |
| url | https://hdl.handle.net/10356/171557 |
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