Grouper FTR14 negatively regulates inflammatory response by targeting TRAF4 and TRAF6

Accumulated evidence indicates that tripartite motif (TRIM) family proteins play crucial roles in host antiviral defense. Notably, the functions of members of fish-specific TRIM (FTR, also known as finTRIM) subfamily remained largely unknown. Our recent results revealed that grouper FTR14 (EcFTR14) could negatively regulate interferon response by targeting TBK1-IRF3 axis. In this study, the regulatory mechanism underlying the action of EcFTR14 on host inflammatory response was elucidated. Using yeast two-hybrid screening, we found that EcFTR14 interacted with EcTRAF4 and EcTRAF6 which was further confirmed by Co-immunoprecipitation (Co-IP) assay. EcFTR14 could recruit the interacting proteins for their co-localization in vitro. Moreover, EcFTR14 hindered the activation of the NF-κB promoter induced by EcTRAF6, but enhanced the inhibitory effect of EcTRAF4. Consistently, overexpression of EcFTR14 significantly reduced the transcriptional levels of pro-inflammatory factors induced by EcTRAF6. Additionally, EcFTR14 degraded EcTRAF6 via the ubiquitin-proteasome pathway, leading to the abatement of EcTRAF6-induced antiviral effects. Conversely, overexpression of EcFTR14 enhanced the pro-viral effect of EcTRAF4. Together, our results suggested that EcFTR14 could negatively regulate the inflammatory response by targeting TRAF4/6, which might be an alternative mechanism for its function as a pro-viral factor.