Please use this identifier to cite or link to this item: https://doi.org/10.1038/ncomms15865
Title: E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP
Authors: Bist P. 
Cheong W.S. 
Ng A.
Dikshit N. 
Kim B.-H.
Pulloor N.K. 
Khameneh H.J.
Hedl M.
Shenoy A.R.
Balamuralidhar V. 
Malik N.B.A. 
Hong M. 
Neutzner A.
Chin K.-C.
Kobayashi K.S.
Bertoletti A. 
Mortellaro A.
Abraham C.
MacMicking J.D.
Xavier R.J.
Sukumaran B. 
Keywords: caspase recruitment domain protein 15
immunoglobulin enhancer binding protein
muramyl dipeptide
protein
protein rip2
protein znrf4
transcription factor RelA
ubiquitin protein ligase E3
unclassified drug
caspase recruitment domain protein 15
DNA binding protein
immunoglobulin enhancer binding protein
n acetylmuramylalanyl dextro isoglutamine
NOD2 protein, human
receptor interacting protein serine threonine kinase 2
RIPK2 protein, human
ZNRF4 protein, human
Znrf4 protein, mouse
bacterial disease
biodegradation
cell organelle
cells and cell components
enzyme
enzyme activity
immune response
immunity
peptide
protein
rodent
animal experiment
Article
caspase activation and recruitment domain
controlled study
cytokine release
cytokine response
endoplasmic reticulum
human
human cell
immunity
in vitro study
in vivo study
monocyte
mouse
nonhuman
protein degradation
protein localization
protein protein interaction
regulatory mechanism
signal transduction
ubiquitination
animal
C57BL mouse
drug effect
genetics
HEK293 cell line
immunological tolerance
immunology
Listeria monocytogenes
listeriosis
metabolism
mutant mouse strain
pathogenicity
physiology
signal transduction
Bacteria (microorganisms)
Listeria monocytogenes
Mus
Acetylmuramyl-Alanyl-Isoglutamine
Animals
DNA-Binding Proteins
HEK293 Cells
Humans
Immune Tolerance
Listeria monocytogenes
Listeriosis
Mice, Inbred C57BL
Mice, Mutant Strains
Monocytes
NF-kappa B
Nod2 Signaling Adaptor Protein
Receptor-Interacting Protein Serine-Threonine Kinase 2
Signal Transduction
Ubiquitination
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Bist P., Cheong W.S., Ng A., Dikshit N., Kim B.-H., Pulloor N.K., Khameneh H.J., Hedl M., Shenoy A.R., Balamuralidhar V., Malik N.B.A., Hong M., Neutzner A., Chin K.-C., Kobayashi K.S., Bertoletti A., Mortellaro A., Abraham C., MacMicking J.D., Xavier R.J., Sukumaran B. (2017). E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. Nature Communications 8 : 15865. ScholarBank@NUS Repository. https://doi.org/10.1038/ncomms15865
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 55 unstimulated and muramyl dipeptide-stimulated conditions. Znrf4 knockdown monocytes have sustained nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) 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-?B, 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. © The Author(s) 2017.
Source Title: Nature Communications
URI: https://scholarbank.nus.edu.sg/handle/10635/174491
ISSN: 2041-1723
DOI: 10.1038/ncomms15865
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