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

Pradeep Bist, Wan Shoo Cheong, Aylwin Ng, Neha Dikshit, Bae-Hoon Kim, Niyas Kudukkil Pulloor, Hanif Javanmard Khameneh, Matija Hedl, Avinash R. Shenoy, Vanniarajan Balamuralidhar, Najib Bin Abdul Malik, Michelle Hong, Albert Neutzner, Keh-Chuang Chin, Koichi S. Kobayashi, Antonio Bertoletti, Alessandra Mortellaro, Clara Abraham, John D. MacMicking, Ramnik J. Xavier and Bindu Sukumaran ()
Additional contact information
Pradeep Bist: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Wan Shoo Cheong: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Aylwin Ng: Gastrointestinal Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Neha Dikshit: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Bae-Hoon Kim: HHMI, Yale Systems Biology Institute, Yale University School of Medicine
Niyas Kudukkil Pulloor: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Hanif Javanmard Khameneh: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Matija Hedl: Yale University School of Medicine
Avinash R. Shenoy: HHMI, Yale Systems Biology Institute, Yale University School of Medicine
Vanniarajan Balamuralidhar: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Najib Bin Abdul Malik: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Michelle Hong: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Albert Neutzner: University Hospital Basel
Keh-Chuang Chin: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Koichi S. Kobayashi: Texas A&M Health Science Centre
Antonio Bertoletti: Program in Emerging Infectious Diseases, Duke-NUS Medical School
Alessandra Mortellaro: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Clara Abraham: Yale University School of Medicine
John D. MacMicking: HHMI, Yale Systems Biology Institute, Yale University School of Medicine
Ramnik J. Xavier: Gastrointestinal Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School
Bindu Sukumaran: Program in Emerging Infectious Diseases, Duke-NUS Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15865

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