E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP

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Title: E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP
Author(s): Bist, P
Cheong, WS
Ng, A
Dikshit, N
Kim, B-H
Pulloor, NK
Khameneh, HJ
Hedl, M
Shenoy, AR
Balamuralidhar, V
Malik, NBA
Hong, M
Neutzner, A
Chin, K-C
Kobayashi, KS
Bertoletti, A
Mortellaro, A
Abraham, C
MacMicking, JD
Xavier, RJ
Sukumaran, B
Item Type: Journal Article
Abstract: 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.
Publication Date: 28-Jun-2017
Date of Acceptance: 12-May-2017
URI: http://hdl.handle.net/10044/1/50102
DOI: https://dx.doi.org/10.1038/ncomms15865
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 8
Copyright Statement: © The Author(s) 2017. his 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/
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NF-KAPPA-B
INNATE IMMUNITY
MEDIATES TOLERANCE
GENOME-WIDE
RIP2
RECEPTOR
INFLAMMATION
STIMULATION
SPECIFICITY
MACROPHAGES
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NF-KAPPA-B
INNATE IMMUNITY
MEDIATES TOLERANCE
GENOME-WIDE
RIP2
RECEPTOR
INFLAMMATION
STIMULATION
SPECIFICITY
MACROPHAGES
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 15865
Appears in Collections:Department of Medicine
Faculty of Medicine



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