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.
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.
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:
- American Type Culture Collection
- DEAD/DEAH box helicase domain
- day postfertilization
- day postinfection
- epithelioma papulosum cyprini
- human embryonic kidney 293T
- human cervical carcinoma
- helicase C-terminal domain
- hour postinfection
- multiplicity of infection
- nucleotide oligomerization domain–like receptor
- open reading frame
- pattern recognition receptor
- quantitative real-time PCR
- regulatory domain
- RIG-like receptor
- respiratory syncytial virus
- spring viremia of carp virus
- Received June 19, 2019.
- Accepted February 7, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.