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E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP
Optimal regulation of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is essential for controlling bacterial infections and inflammatory disorders. Chronic NOD2 stimulation induces non-responsiveness to restimulation, termed NOD2-induced tolerance. Al...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493756/ https://www.ncbi.nlm.nih.gov/pubmed/28656966 http://dx.doi.org/10.1038/ncomms15865 |
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author | Bist, Pradeep Cheong, Wan Shoo Ng, Aylwin Dikshit, Neha Kim, Bae-Hoon Pulloor, Niyas Kudukkil Khameneh, Hanif Javanmard Hedl, Matija Shenoy, Avinash R. Balamuralidhar, Vanniarajan Malik, Najib Bin Abdul Hong, Michelle Neutzner, Albert Chin, Keh-Chuang Kobayashi, Koichi S. Bertoletti, Antonio Mortellaro, Alessandra Abraham, Clara MacMicking, John D. Xavier, Ramnik J. Sukumaran, Bindu |
author_facet | Bist, Pradeep Cheong, Wan Shoo Ng, Aylwin Dikshit, Neha Kim, Bae-Hoon Pulloor, Niyas Kudukkil Khameneh, Hanif Javanmard Hedl, Matija Shenoy, Avinash R. Balamuralidhar, Vanniarajan Malik, Najib Bin Abdul Hong, Michelle Neutzner, Albert Chin, Keh-Chuang Kobayashi, Koichi S. Bertoletti, Antonio Mortellaro, Alessandra Abraham, Clara MacMicking, John D. Xavier, Ramnik J. Sukumaran, Bindu |
author_sort | Bist, Pradeep |
collection | PubMed |
description | Optimal regulation of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is essential for controlling bacterial infections and inflammatory disorders. Chronic NOD2 stimulation induces non-responsiveness to restimulation, termed NOD2-induced tolerance. Although the levels of the NOD2 adaptor, RIP2, are reported to regulate both acute and chronic NOD2 signalling, how RIP2 levels are modulated is unclear. Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation. A fraction of RIP2 localizes to the endoplasmic reticulum (ER), where it interacts with ZNRF4 under either unstimulated and muramyl dipeptide-stimulated conditions. Znrf4 knockdown monocytes have sustained nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and Znrf4 knockdown mice have reduced NOD2-induced tolerance and more effective control of Listeria monocytogenes infection. Our results thus demonstrate E3-ubiquitin ligase ZNRF4-mediated RIP2 degradation as a negative regulatory mechanism of NOD2-induced NF-κB, cytokine and anti-bacterial responses in vitro and in vivo, and identify a ZNRF4-RIP2 axis of fine-tuning NOD2 signalling to promote protective host immunity. |
format | Online Article Text |
id | pubmed-5493756 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54937562017-07-11 E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP Bist, Pradeep Cheong, Wan Shoo Ng, Aylwin Dikshit, Neha Kim, Bae-Hoon Pulloor, Niyas Kudukkil Khameneh, Hanif Javanmard Hedl, Matija Shenoy, Avinash R. Balamuralidhar, Vanniarajan Malik, Najib Bin Abdul Hong, Michelle Neutzner, Albert Chin, Keh-Chuang Kobayashi, Koichi S. Bertoletti, Antonio Mortellaro, Alessandra Abraham, Clara MacMicking, John D. Xavier, Ramnik J. Sukumaran, Bindu Nat Commun Article Optimal regulation of the innate immune receptor nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is essential for controlling bacterial infections and inflammatory disorders. Chronic NOD2 stimulation induces non-responsiveness to restimulation, termed NOD2-induced tolerance. Although the levels of the NOD2 adaptor, RIP2, are reported to regulate both acute and chronic NOD2 signalling, how RIP2 levels are modulated is unclear. Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation. A fraction of RIP2 localizes to the endoplasmic reticulum (ER), where it interacts with ZNRF4 under either unstimulated and muramyl dipeptide-stimulated conditions. Znrf4 knockdown monocytes have sustained nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and Znrf4 knockdown mice have reduced NOD2-induced tolerance and more effective control of Listeria monocytogenes infection. Our results thus demonstrate E3-ubiquitin ligase ZNRF4-mediated RIP2 degradation as a negative regulatory mechanism of NOD2-induced NF-κB, cytokine and anti-bacterial responses in vitro and in vivo, and identify a ZNRF4-RIP2 axis of fine-tuning NOD2 signalling to promote protective host immunity. Nature Publishing Group 2017-06-28 /pmc/articles/PMC5493756/ /pubmed/28656966 http://dx.doi.org/10.1038/ncomms15865 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Bist, Pradeep Cheong, Wan Shoo Ng, Aylwin Dikshit, Neha Kim, Bae-Hoon Pulloor, Niyas Kudukkil Khameneh, Hanif Javanmard Hedl, Matija Shenoy, Avinash R. Balamuralidhar, Vanniarajan Malik, Najib Bin Abdul Hong, Michelle Neutzner, Albert Chin, Keh-Chuang Kobayashi, Koichi S. Bertoletti, Antonio Mortellaro, Alessandra Abraham, Clara MacMicking, John D. Xavier, Ramnik J. Sukumaran, Bindu E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title | E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title_full | E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title_fullStr | E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title_full_unstemmed | E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title_short | E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP |
title_sort | e3 ubiquitin ligase znrf4 negatively regulates nod2 signalling and induces tolerance to mdp |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493756/ https://www.ncbi.nlm.nih.gov/pubmed/28656966 http://dx.doi.org/10.1038/ncomms15865 |
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