Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKe by TRAFs that were pre-associated with TBK1/IKKe via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKe. TRAF2−/−3−/−5−/−6−/− cells completely lost RNA virus responses. TRAFs’ E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-κB and TBK1/IKKe activation. NEMO-activated IKKα/β were important for TBK1/IKKe activation through IKKα/β-mediated TBK1/IKKe phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKe activation and thus fine-tuned antiviral immunity under physiological conditions.

/pdf/mavs-activates-tbk1-and-ikke-through-trafs-in-nemo-dependent-2xnyqy9yjq.pdf

MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner.

Summary
Retinoic acid-inducible gene I (RIG-I) -like receptors (RLRs) are found conservatively present in teleost fish. All three members, RIG-I, MDA5 and LGP2, together with the downstream molecules such as MITA, TRAF3 and TBK1, have been identified in a range of fish species. However, it is unexpected that RIG-I has not been reported in fish of Acanthopterygii, and it would be important to clarify the presence and role of the RIG-I gene in a broad range of taxa in Teleostei. RLRs in fish can be induced in vivo and in vitro by viral pathogens as well as synthetic dsRNA, poly(I:C), leading to the production of type I interferons (IFNs) and the expression of IFN-stimulated genes (ISGs). Bacterial pathogens, such as Edwardsiella tarda, and their components, such as lipopolysaccharide are also found to induce the expression of RLRs, and whether such induction was mediated through the direct recognition by RLRs or through crosstalk with other pattern recognition receptors recognizing directly bacterial pathogen-associated molecular patterns awaits to be investigated. On the other hand, RLR-activated type I IFN production can be negatively regulated in fish by molecules, such as TBK-1-like protein and IRF10, which are found to negatively regulate RIG-I and MAVS-activated type I IFN production, and to block MITA or bind ISRE motifs, respectively. It is considered that the evolutionary occurrence of RLRs in fish, and their recognized ligands, especially those from their fish pathogens, as well as the mechanisms involved in the RLR signalling pathways, are of significant interest for further investigation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12714

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) in fish: current knowledge and future perspectives.

Interferons (IFNs) have been reported in vertebrates from fish to mammals. To date, two types of IFNs, i.e. type I and type II IFNs have been reported in a range of fish species in aquaculture. In fish, type I IFNs are clarified into group I and group II, with two cysteines and four cysteines, and further into subgroups a, d, e, h, and b, c, f, respectively. Group I IFNs appear to exist in all fish species, whereas group II IFNs are discovered only in certain species such as cyprinids, salmonids and perciform fish. It seems preferentially functional that group I IFNs signal through cytokine receptor family B (CRFB) 5 and CRFB1, while group II IFNs through CRFB5 and CRFB2. But they all initiate a same signalling pathway for the expression of interferon induced genes. The information about the production and the function of type I IFNs in fish are further summarized in the review. Interestingly, two members of type II IFNs, IFN-gamma and a unique member, IFN-gamma related gene (IFN-gamma rel) exist in fish, and IFN-gamma and IFN-gamma rel can separately become homodimers for signalling through CRFB13, CRFB17, CRFB6 and CRFB17, respectively. In addition, the variation in the composition of type I and type II IFNs as well as in their receptors in some cyprinid and salmonid fish has also been reviewed. It is suggested that future perspectives for the research on type I and type II IFNs in fish are outlined from a comparative and evolutionary point of view.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/raq.12349

Fish type I and type II interferons: composition, receptor usage, production and function

Insight into the heat resistance of fish via blood: effects of heat stress on metabolism, oxidative stress and antioxidant response of olive flounder Paralichthys olivaceus and turbot Scophthalmus maximus.

Identification and characterization of MAVS from black carp Mylopharyngodon piceus.

CARD and TM of MAVS of black carp play the key role in its self-association and antiviral ability.

Triploid hybrid (3n = 150) of red crucian carp (♀, 2n = 100) and allotetraploid (♂, 4n = 200) display improved disease resistance and stress resistance than their parents. In order to elucidate their innate immune mechanisms, three novel cell lines from the caudal fin of red crucian carp, triploid hybrid and allotetraploid (named 2nFC, 3nFC and 4nFC accordingly) were established and characterized respectively. 2nFC, 3nFC and 4nFC showed fibroblast-like morphology and characteristics. They have been subcultured for more than 100 passages since the initial primary culture. Viral infection experiments showed that 2nFC, 3nFC and 4nFC were susceptible to spring viraemia of carp virus (SVCV) infection. Intriguingly, 3nFC performed the stronger resistance ability against SVCV than 2nFC and 4nFC, which indicated that 2nFC, 3nFC and 4nFC might be used as the suitable in vitro models for exploring and analyzing the differences among these three cyprinid fishes in antiviral innate immune mechanisms. Based on this, we analyzed the transcriptome profile of 2nFC, 3nFC and 4nFC in the context of SVCV infection. The KEGG enrichment analysis showed that the differentially expressed genes (DEGs) were primarily enriched to immune-related signaling pathways. However, some signaling pathways against viral infection were activated remarkably in 2nFC and 3nFC but not in 4nFC. Overall, the establishment of 2nFC, 3nFC and 4nFC provided us a suitable platform to elucidate the innate immunity of fishes with different ploidy and clear genetic relationship.

Establishment of fin cell lines and their use to study the immune gene expression in cyprinid fishes with different ploidy in rhabdovirus infection.

The Kaposi’s Sarcoma-associated Herpesvirus (KSHV)-encoded G-protein coupled receptor (vGPCR) is an oncoprotein that is implicated in KSHV-associated malignancies. We previously revealed vGPCR incorporates sulfate groups within its extracellular N-terminal tyrosine residues (Y26 and Y28) and that this tyrosine sulfation is crucial for its tumorigenicity in nude mice. hGRO-α binds vGPCR in a sulfotyrosine-dependent manner and promotes its tumorigenicity through autocrine signaling. Interestingly, an unsulfated vGPCR mutant (yydd-vGPCR) attenuated the tumor growth triggered by hGRO-α. In this study, the extracellular N-terminus of vGPCR (wt-vGN) and an unsulfated vGPCR mutant (yydd-vGN) were individually secreted, expressed and purified. A radioactive labeling assay demonstrated that wt-vGN but not yydd-vGN incorporated [35S]-sulfate. In nude mice, NIH3T3 cells expressing yydd-vGN but not wt-vGN could significantly inhibit the tumor growth triggered by hGRO-α. All our data support the conclusion that the unsulfated extracellular N-terminus of vGPCR reduces the tumorigenicity of hGRO-α.

/pdf/the-unsulfated-extracellular-n-terminus-of-vgpcr-reduces-the-3zszg78epi.pdf

The unsulfated extracellular N-terminus of vGPCR reduces the tumorigenicity of hGRO-α in nude mice

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Identification and characterization of MAVS from black carp Mylopharyngodon piceus.

CARD and TM of MAVS of black carp play the key role in its self-association and antiviral ability.

Establishment of fin cell lines and their use to study the immune gene expression in cyprinid fishes with different ploidy in rhabdovirus infection.

The unsulfated extracellular N-terminus of vGPCR reduces the tumorigenicity of hGRO-α in nude mice