A finTRIM Family Protein Acquires RNA-Binding Activity and E3 Ligase Activity to Shape the IFN Response in Fish [INNATE IMMUNITY AND INFLAMMATION]

Key Points

FTRCA1 is a fish-specific E3 ligase with RNA-binding activity.

FTRCA1 impairs STING1 and IRF7 mRNA levels to downregulate the IFN response.

FTRCA1 targets TBK1 protein degradation to downregulate the IFN response.

Abstract

Tripartite motif (TRIM) family proteins have come forth as important modulators of innate signaling dependent on of E3 ligase activity. Recently, several human TRIM proteins have been identified as unorthodox RNA-binding proteins by RNA interactome analyses; however, their targets and functions remain largely unknown. FTRCA1 is a crucian carp (Carassius auratus)–specific finTRIM (fish novel TRIM) member and negatively regulates the IFN antiviral response by targeting two retinoic acid–inducible gene-I (RIG-I)–like receptor (RLR) pathway molecules, that is, TANK-binding kinase 1 (TBK1) and IFN regulatory factor 7 (IRF7). In this study, we identify FTRCA1 as an RNA-binding E3 ligase and characterize the contribution of its RNA-binding activity and E3 ligase activity to fish IFN response. Besides targeting TBK1 and IRF7, FTRCA1 downregulates fish IFN response also by targeting stimulator of IFN response cGAMP interactor 1 (STING1). E3 ligase activity is required for full inhibition on the TBK1- and IRF7-mediated IFN response, but partial inhibition on the STING1-mediated IFN response. However, FTRCA1 has a general binding potential to mRNAs in vitro, it selectively binds STING1 and IRF7 mRNAs in vivo to attenuate mRNA levels, and it directly interacts with TBK1 protein to target protein degradation for downregulating the IFN response. Our results present an interesting example of a fish species–specific finTRIM protein that has acquired RNA-binding activity and E3 ligase activity to fine-tune fish IFN response.

Footnotes

This work was supported by National Key R&D Program of China Grant 2018YFD0900302, Strategic Priority Research Program of the Chinese Academy of Sciences Grant XDA24010308, National Natural Science Foundation Grant 31972826, and by Application Fundamental Frontier Special Project of Wuhan Grant 2020020601012256.

The online version of this article contains supplemental material.

Abbreviations used in this article:

CABC. auratus L. blastulaCo-IPcoimmunoprecipitationCCcoiled-coil domainEPCepithelioma papulosum cyprinifinTRIMfish novel TRIMFTRCA1finTRIM C. auratus 1HAhemagglutininIRFIFN regulatory factorISGIFN-stimulated geneMDA5melanoma differentiation-associated Ag 5NCnegative controlNP-40Nonidet P-40ORFopen reading frameP-bodyprocessing bodyPEIpolyethyleniminepoly(I:C)polyinosinic:polycytidylic acidqPCRquantitative PCRRBDRNA-binding domainRBPRNA-binding proteinRIG-Iretinoic acid–inducible gene-IRINGreally interesting new geneRIPRNA immunoprecipitationRISCRNA-induced silencing complexRLRRIG-I–like receptorsiRNAsmall interfering RNASTING1mediator of IRF3 activatorTBK1TANK-binding kinase 1TRIMtripartite motifReceived May 10, 2022.Accepted June 25, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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