2. Academic Validation
  3. E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP

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

  • Nat Commun. 2017 Jun 28;8:15865. doi: 10.1038/ncomms15865.
Pradeep Bist 1,  Wan Shoo Cheong 1,  Aylwin Ng 2 3,  Neha Dikshit 1,  Bae-Hoon Kim 4,  Niyas Kudukkil Pulloor 1,  Hanif Javanmard Khameneh 5,  Matija Hedl 6,  Avinash R Shenoy 4 7,  Vanniarajan Balamuralidhar 1,  Najib Bin Abdul Malik 1,  Michelle Hong 1,  Albert Neutzner 8,  Keh-Chuang Chin 5 9 10,  Koichi S Kobayashi 11,  Antonio Bertoletti 1,  Alessandra Mortellaro 5,  Clara Abraham 6,  John D MacMicking 4,  Ramnik J Xavier 2 3,  Bindu Sukumaran 1
Affiliations

Affiliations

  • 1 Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 2 Gastrointestinal Unit, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
  • 3 Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
  • 4 HHMI, Yale Systems Biology Institute, Departments of Microbial Pathogenesis and Immunobiology, Yale University School of Medicine, New Haven, Connecticut 065207, USA.
  • 5 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
  • 6 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
  • 7 Medical Research Council Centre for Molecular Bacteriology &Infection, Armstrong Rd, Imperial College, London SW7 2AZ, UK.
  • 8 Department of Biomedicine, University Hospital Basel, Basel 4031, Switzerland.
  • 9 Department of Physiology, Yong Loo Lin School of Medicine, Singapore 117593, Singapore.
  • 10 Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore.
  • 11 Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Centre, College Station, Texas 77843-1114, USA.
PMID: 28656966 DOI: 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-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.

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