RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize "immune-cold" tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy. 

/pdf/exploiting-rig-i-like-receptor-pathway-for-cancer-1hglwrog.pdf

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

http://www.cell.com/article/S2589004222010938/pdf

LGP2 is essential for zebrafish survival through dual regulation of IFN antiviral response

Molecular characterization of the interferon regulatory factor (IRF) family and functional analysis of IRF11 in the large yellow croaker (Larimichthys crocea)

Recent studies have related the membrane-associated RING-CH-type finger (MARCH) family proteins to host innate immune response. Zebrafish (Danio rerio) MARCH8 is reported to target SVCV glycoprotein for degradation; however, little is known about whether fish MARCH8 is involved in innate interferon (IFN) response. In this study, zebrafish march8 was significantly induced by SVCV infection. Overexpression of MARCH8 diminished fish IFN-mediated antiviral response, thus promoting the replication of SVCV and GCRV in fish cells. Mechanistically, MARCH8 interacts with and degrades MITA and TBK1 proteins to inhibit IFN response. Moreover, MARCH8 has an E3 ligase activity and enhances MITA and TBK1 polyubiquitination. Our findings reveal a mechanism whereby zebrafish MARCH8 downregulates fish IFN response and facilitates viral replication by targeting MITA and TBK1 for protein degradation. 

Zebrafish MARCH8 downregulates fish IFN response by targeting MITA and TBK1 for protein degradation.

Heterosis versus breakdown in fish hybrids revealed by one-parental species-associated viral infection

In mammals, transcription factors of IFN-regulatory factors (IRFs) family translate viral recognition into IFN antiviral responses through translocating to nucleus and subsequently binding to the promoters of IFN and IFN-stimulated genes (ISGs). In addition to IRF1-9 conserved across vertebrates and IRF10 in teleost fish and bird, teleost fish has another novel member, IRF11; however, little is known about its role in IFN response. In this study, we provide evidence that IRF11 is present only in Osteichthyes (bony fish) but lost in tetrapods and subsequently characterize the stimulatory potential of zebrafish IRF11 to IFN antiviral response relevant to its subcellular localization and promoter binding. Overexpression of zebrafish IRF11 restricts virus replication through induction of IFN and ISGs. Zebrafish IRF11 is constitutively localized to nucleus, which is driven by a tripartite NLS motif, consisting of three interdependent basic clusters, two in DNA binding domain (DBD) and one in the region immediately C-terminal to DBD. Nuclear IRF11 binds to the IRF-binding element/IFN-stimulated response element motifs of zebrafish IFN promoters depending on the two conserved amino acids (K78, R82) within DBD helix α3. K78 and R82 also benefit zebrafish IRF11 nuclear import as two key residues positioned at the first basic cluster of the tripartite NLS motif. Such features enable zebrafish IRF11 to function as a positive transcription factor for fish IFN antiviral response. Our results identify a unique tripartite NLS motif that integrates DNA-binding activity and nuclear import ability, allowing zebrafish IRF11 to initiate IFN and ISG expression.

Characterization of DNA Binding and Nuclear Retention Identifies Zebrafish IRF11 as a Positive Regulator of IFN Antiviral Response.

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. 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.

A finTRIM Family Protein Acquires RNA-Binding Activity and E3 Ligase Activity to Shape the IFN Response in Fish

In mammals, tripartite motif (TRIM)-containing proteins are involved in interferon (IFN)-mediated antiviral response as pivotal players endowed with antiviral effects and modulatory capacity. Teleost fish have a unique subfamily of TRIM, called finTRIM (fish novel TRIM, FTR) generated by genus- or species-specific duplication of TRIM genes. Herein, four TRIM genes are identified from Epithelioma papulosum cyprini (EPC) cells, and phylogenetically close to the members of finTRIM, thus named FTREPC1, FTREPC2, FTREPC3 and FTREPC4. Despite high similarity in nucleotide sequence, FTREPC1/2 genes encode two proteins with a typically consecutive tripartite motif followed by a C-terminal B30.2 domain, while FTREPC3/4-encoding proteins retain only a RING domain due to early termination of translation. They are induced by poly(I:C), GCRV and SVCV as IFN-stimulated genes (ISGs), and this induction is severely impaired by blockade of STAT1 pathway and is dependent on a typical ISRE motif within the 5' untranslated regions (5'UTRs) of FTREPC1/2/3/4 genes. Whereas overexpression of FTREPC1/2/3/4 alone does not activate fish IFN promoters, overexpression of FTREPC1 or FTREPC2, rather than FTREPC3 and FTREPC4, significantly impairs intracellular poly(I:C)-triggered activation of fish IFN promoters. Consistently, FTREPC1/2 promote virus replication through negatively regulating IFN response. Our results provide evidence for the involvement of EPC finTRIM proteins in IFN antiviral response and insights into genus- or species-specific regulation of fish innate immune pathways.

Molecular identification and function characterization of four finTRIM genes from the immortal fish cell line, EPC

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