NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the Interaction of MDA5 and MAVS [INNATE IMMUNITY AND INFLAMMATION]

Key Points

  • NOD1 restricts replication of RNA viruses.

  • The cumulative effects between NOD1 and MDA5 normal form are conserved.

  • NOD1 degradation by the truncated form of MDA5 is specific to fish.

Visual Abstract

Figure1

Abstract

Nucleotide oligomerization domain–like receptors (NLRs) and RIG-I–like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus–infected NOD1−/− zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5–MAVS and TRAF3–MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(I:C) and the formation of the MDA5a–MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1–MDA5 and NOD1–TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(I:C) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form–mediated immune signaling in vertebrates.

Footnotes

  • This work was supported by Strategic Priority Research Program of the Chinese Academy of Sciences Grant XDA24010308, the National Natural Science Foundation of China (31672687 and 31873046), and the Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province of China (2018CFA011). The sponsors played no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    ATCC
    American Type Culture Collection
    co-IP
    coimmunoprecipitation
    DExDc
    DEAD/DEAH box helicase domain
    dpf
    day postfertilization
    dpi
    day postinfection
    EPC
    epithelioma papulosum cyprini
    h
    human
    HEK293T
    human embryonic kidney 293T
    Hela
    human cervical carcinoma
    HELICc
    helicase C-terminal domain
    hpi
    hour postinfection
    IP
    immunoprecipitation
    MO
    morpholino
    MOI
    multiplicity of infection
    NLR
    nucleotide oligomerization domain–like receptor
    ORF
    open reading frame
    PRR
    pattern recognition receptor
    qRT-PCR
    quantitative real-time PCR
    RD
    regulatory domain
    RLR
    RIG-like receptor
    RSV
    respiratory syncytial virus
    SVCV
    spring viremia of carp virus
    WT
    wild-type.
  • Received June 19, 2019.
  • Accepted February 7, 2020.

This content is also available in: Español Português

Do NOT follow this link or you will be banned from the site!