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.
Highlights
Upon pathogen invasion, host immune response starts with detection of microbial products by pattern recognition receptor (PRR), leading to cell activation and synthesis of inflammatory cytokines
Antiviral Tripartite motif (TRIM) have been involved in multiple types of mechanisms, and recent large-scale functional studies revealed that TRIMs are frequently modulators rather than direct effectors of antiviral immunity [21, 47]
Since TRIM proteins are involved in many basic cellular functions, whether their implication in antiviral mechanisms is a primordial feature of the family has remained an open question
Summary
Host immune response starts with detection of microbial products by pattern recognition receptor (PRR), leading to cell activation and synthesis of inflammatory cytokines. Many tripartite motif (TRIM) proteins are important antiviral factors involved in antiviral defense via multiple mechanisms: as direct effectors often induced by type I IFN, or as modulators/ enhancers of the response [4]. FinTRIMs, which constitute the largest TRIM expansion observed in zebrafish, are likely involved in antiviral defenses These TRIMs, which have an RBCC-B30.2 domain structure, were initially discovered in salmonids as genes induced by the rhabdovirus VHSV in leukocytes ex vivo [35]. Two members of the family (ftr and ftr83) did not follow this pattern: they had orthologs in the main fish branches [28], indicating that they were likely related to the basal (i.e., ancestral) finTRIM genes They were expressed at a higher constitutive level in multiple tissues of zebrafish larvae and were not induced by viral infection or IFN treatment. Our data show that positive regulation of the IFN pathway and antiviral functions are a fundamental property of finTRIMs, and more generally of TRIM proteins across vertebrate immune systems
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
