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The NLRP4-DTX4 axis: a key suppressor of TBK1 and innate antiviral signaling

Cellular & Molecular Immunology volume 9, pages 431–433 (2012)Cite this article

The innate immune system provides the first line of defense for protection against pathogenic bacteria or viruses. The host ‘senses’ pathogen infection by recognition of pathogen-associated molecular patterns via germ-line-encoded pattern-recognition receptors including Toll-like receptors, RIG-I-like receptors (RLRs), NOD-like receptors (NLRs) and DNA sensors. Upon receptor engagement, signaling cascade events culminate in the production of the type I interferons (IFNs) IFN-α and IFN-β that restrict virus replication. RIG-I and MDA5 are the key RLRs that recognize viral genomic RNAs and transmit downstream signals to the mitochondrial adaptor molecule MAVS (also known as IPS-1, VISA or Cardif).1 MAVS nucleates a signaling complex anchored to the mitochondria containing the E3 ubiquitin ligase TRAF3, the non-canonical IκB kinases (IKKs) TBK1 and IKKi (also known as IKK epsilon) and the adaptor molecules NEMO (also known as IKK gamma) and TANK.1 TBK1 and IKKi phosphorylate the interferon regulatory factor 3 (IRF3) transcription factor to trigger IRF3 dimerization and nuclear localization to activate type I IFN transcription.2 TBK1 and IKKi are both regulated by posttranslational modifications that occur during virus infection including lysine 63 (K63)-linked polyubiquitination by TRAF3 or other E3 ubiquitin ligases.3,4 TBK1/IKKi K63-linked polyubiquitination is linked to their activation and may be involved in recruiting signaling complexes containing ubiquitin-binding domains to transmit downstream signals. Dysregulation of type I IFN signaling, characterized by overproduction of IFN-α and IFN-β, has been implicated in numerous autoimmune diseases such as systemic lupus erythematosus.5 Therefore, the production of IFN is subject to tight regulatory control by numerous mechanisms to maintain immune homeostasis. In a recent article in Nature Immunology, Cui et al.6 have reported that the NLR protein NLRP4 functions as a negative regulator in the RLR pathway by targeting TBK1 for proteasomal degradation.

NLRs represent a family of innate immune regulatory proteins that consist of a nucleotide-binding and oligomerization (NOD) domain, a leucine-rich repeat region and a variable amino-terminal effector domain. NLRs may function as either activators or negative regulators of the RLR signaling pathway.7 NLRP4, an NLR family member, has been reported to inhibit the nuclear factor-κB signaling pathway; however, its role in the RLR pathway was not previously examined.8 The authors initially performed an overexpression screen using vectors encoding various NLRs and identified NLRP4 as an inhibitor of RLR signaling.6 NLRP4 inhibited the induction of IFN-β and ISRE luciferase reporters by poly(I:C) (double-stranded RNA mimic), poly(dA:dT) (double-stranded DNA mimic) and vesicular stomatitis virus-GFP infection. Knockdown of NLRP4 by RNA interference potentiated the activation of IFN-β and ISRE luciferase reporters in 293T cells. Furthermore, the authors used more physiologically relevant immune cells including monocytic THP-1 cells and peripheral blood mononuclear cells to demonstrate that knockdown of NLRP4 enhanced the expression of interferon stimulated genes generated during virus infection.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, The University of Miami, Miller School of Medicine, Miami, 33136, FL, USA

    Soratree Charoenthongtrakul

  2. Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami, 33136, FL, USA

    Linlin Gao

  3. Department of Oncology, Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, 21287, MD, USA

    Edward W Harhaj

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  1. Soratree Charoenthongtrakul
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Correspondence to Edward W Harhaj.

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Charoenthongtrakul, S., Gao, L. & Harhaj, E. The NLRP4-DTX4 axis: a key suppressor of TBK1 and innate antiviral signaling. Cell Mol Immunol 9, 431–433 (2012). https://doi.org/10.1038/cmi.2012.49

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