FTR83, a Member of the Large Fish-Specific finTRIM Family, Triggers IFN Pathway and Counters Viral Infection

Abstract

Tripartite motif (TRIM) proteins are involved in various cellular functions and constitute key factors of the antiviral innate immune response. TRIM proteins can bind viral particles directly, sending them to degradation by the proteasome, or ubiquitinate signaling molecules leading to upregulation of innate immunity. TRIM proteins are present in across metazoans but are particularly numerous in vertebrates where genes comprising a B30.2 domain have been often duplicated. In fish, a TRIM subset named finTRIM is highly diversified, with large gene numbers and clear signatures of positive selection in the B30.2 domain suggesting they may be involved in antiviral mechanisms. finTRIM provides a beautiful model to investigate the primordial implication of B30.2 TRIM subsets in the arsenal of vertebrate antiviral defenses. We show here that ftr83, a zebrafish fintrim gene mainly expressed in the gills, skin and pharynx, encodes a protein affording a potent antiviral activity. In vitro, overexpression of FTR83, but not of its close relative FTR82, induced IFN and IFN-stimulated gene expression and afforded protection against different enveloped and non-enveloped RNA viruses. The kinetics of IFN induction paralleled the development of the antiviral activity, which was abolished by a dominant negative IRF3 mutant. In the context of a viral infection, FTR83 potentiated the IFN response. Expression of chimeric proteins in which the B30.2 domain of FTR83 and the non-protective FTR82 had been exchanged, showed that IFN upregulation and antiviral activity requires both the Ring/BBox/Coiled coil domain (supporting E3 ubiquitin ligase) and the B30.2 domain of FTR83. Finally, loss of function experiments in zebrafish embryos confirms that ftr83 mediates antiviral activity in vivo. Our results show that a member of the largest TRIM subset observed in fish upregulates type I IFN response and afford protection against viral infections, supporting that TRIMs are key antiviral factors across vertebrates.

Genetic and transcriptomic analyses provide new insights on the early antiviral response to VHSV in resistant and susceptible rainbow trout

“…The case of fintrim [ 16 , 36 ] is particularly interesting: discovered as VHSV- and IFN- induced genes in rainbow trout leukocytes [ 16 ], they display signatures of positive selection suggesting that they may be involved in the antiviral response [ 36 ]. However, a direct IFN-dependent antiviral activity has been shown for only one member of this large gene family in zebrafish [ 37 ], and it is not clear whether all fintrim are actually involved in the IFN response. Our observations also suggest that a number of fintrim , which are induced similarly in A22 and B57, may play a role in the antiviral defense independently of the IFN response, a possible strategy to counteract viral subversion strategies.…”

“…Our observations also suggest that a number of fintrim , which are induced similarly in A22 and B57, may play a role in the antiviral defense independently of the IFN response, a possible strategy to counteract viral subversion strategies. Further investigations will be necessary to understand the diversity of the antiviral mechanisms mediated by these highly diversified factors [ 37 ].…”

Interferon-stimulated genes in zebrafish and human define an ancient arsenal of antiviral immunity

“…Interestingly, ISGs are found only among the recently diversified, species-specific finTRIMs; the most basal members (ftr82-84), well-conserved among fish, were not found here to be induced by IFNφ1 or by CHIKV, consistent with previous studies (48). Nevertheless, ftr83 appears to mediate protection especially in the gill region by stimulating local ifnphi1 expression (49). The diversity and evolution under positive selection of the IFN-inducible finTRIMs evoke viral recognition (22), yet their functions remain unclear.…”

Molecular Characterization and Expression Analysis of ftr01, ftr42, and ftr58 in Zebrafish (Danio rerio)

“…The RING domain of TRIMs usually mediates interaction with ubiquitin-conjugating enzyme (E2) via zinc finger motifs (Ye and Rape 2009;Ebner et al 2017;Esposito et al 2017). Several studies have shown that the RING domain is essential for the antiviral activity of the TRIM members, including TRIM5a, TRIM56, TRIM41, TRIM25, and ftr83 (Zhang et al 2013;Liu et al 2014;Campbell et al 2015;Yang et al 2016a;Langevin et al 2017). Several TRIM-like members, such as TRIM14 and TRIM16 lack a RING domain within the RBCC (Bell et al 2012;Zhou et al 2014), but fish TRIM16 has a RING domain while not possessing a B-Box domain (Yu et al 2016).…”

“…Overexpression of ftr83 promotes the infection of some RNA viruses, including Infectious hematopoietic necrosis virus (IHNV), viral hemorrhagic septicemia virus (VHSV), and SVCV. However, ftr82 did not play any role in viral infection, although engaged in zebrafish vascular patterning (Chang et al 2017;Langevin et al 2017).…”