PMID:30021903

Citation	Komatsu, T, Tanaka, Y, Kitagawa, Y, Koide, N, Naiki, Y, Morita, N, Gotoh, B and Yokochi, T (2018) Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly. J. Virol. 92
Abstract	Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(-)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(-)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(-)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.
Links	PubMed PMC6146803 Online version:10.1128/JVI.00842-18
Keywords	Caspase 1/genetics; Caspase 1/metabolism; HEK293 Cells; Humans; Inflammasomes/genetics; Inflammasomes/metabolism; Interleukin-1beta/genetics; Interleukin-1beta/secretion; Macrophages/metabolism; Macrophages/pathology; Macrophages/virology; NLR Family, Pyrin Domain-Containing 3 Protein/genetics; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Protein Multimerization/genetics; Respirovirus Infections/genetics; Respirovirus Infections/metabolism; Respirovirus Infections/pathology; Sendai virus/genetics; Sendai virus/metabolism; THP-1 Cells; Viral Proteins/genetics; Viral Proteins/metabolism
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
SENDZ:V		GO:1900226: negative regulation of NLRP3 inflammasome complex assembly	ECO:0000315:		P		Figure 2 shows the inhibition of NLRP3 expression levels in cells infected with Sev V protein/Protein V from Sendai virus is present.	complete CACAO 13434

References

See Help:References for how to manage references in GONUTS.