RIG-I-Like Receptors: Comparison
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Kaposi’s sarcoma-associated herpesvirus (KSHV) and the Epstein–Barr virus (EBV) are double-stranded DNA oncogenic gammaherpesviruses. These two viruses are associated with multiple human malignancies, including both B and T cell lymphomas, as well as epithelial- and endothelial-derived cancers. KSHV and EBV establish a life-long latent infection in the human host with intermittent periods of lytic replication. Infection with these viruses induce the expression of both viral and host RNA transcripts and activates several RNA sensors including RIG-I-like receptors (RLRs).

  • KSHV
  • EBV
  • antiviral response

1. Introduction

KSHV (also known as human herpesvirus 8, HHV8) and EBV (also known as human herpesvirus 4, HHV4) are members of the gammaherpesvirus family and these viruses are associated with multiple human malignancies. KSHV is the etiological agent of Kaposi’s sarcoma (KS), in addition to two B-cell-derived malignancies: primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2][1][2]. More recently, KSHV has also been implicated as a causal agent for osteosarcoma [3]. EBV is linked with B cell lymphomas and epithelial cell carcinomas. They include, but are not limited to, Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), non-Hodgkin lymphoma (NHL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). In addition to its association with human tumors, EBV is also linked to several autoimmune diseases such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS) [4,5,6,7,8][4][5][6][7][8].
EBV and KSHV are oncogenic double-stranded DNA (dsDNA) viruses with both viruses exhibiting two distinct phases of their life cycles: latency and lytic replication. During latency, the KSHV genome is replicated as a circular episome by the cellular DNA polymerase and only expresses a limited set of latency-associated proteins and pre-microRNAs [9]. Similarly, EBV also maintains its genome as a latent episome in the nucleus of the host cell and expresses a small group of viral proteins and a number of viral noncoding RNAs including EBV-encoded RNAs (EBERs) and BamHI-A rightward transcripts (BARTs). Furthermore, EBV establishes distinct types of latency programs (III-II-I-0) in different cell types based on specific latent gene expression patterns [8]. Under certain conditions, both viruses are able to reactivate and enter the lytic cycle. During lytic reactivation, all viral genes are transcribed, viral DNA is amplified, progeny virions are produced, and this eventually leads to the death of reactivating cells [10,11][10][11]. As there are more viral proteins and noncoding RNAs induced during lytic replication, the host’s immune responses tend to be more pronounced during lytic infection compared to latency.
The innate immune response triggered by nucleic acid recognition plays an important role during viral infection. This process is initiated by nucleic acid sensors that recognize foreign DNA and RNA, such as viral genomes. Upon sensing the viral nucleic acids, the DNA/RNA sensors and their signaling cascades are activated to produce type I interferons (IFNs) and proinflammatory cytokines, which establish an antiviral state and inhibit viral infection. Several host DNA and RNA sensors have been reported to limit KSHV or EBV infection, including endosomal Toll-like receptors (TLRs), cytosolic DNA and dsRNA sensors cyclic GMP–AMP synthase (cGAS) and retinoic acid-inducible gene I protein (RIG-I)-like receptors (RLRs) [12,13][12][13]. RLRs encompass two major dsRNA sensors of the innate immune system, RIG-I and melanoma differentiation-associated gene 5 (MDA5). Upon binding to their dsRNA ligand, RIG-I/MDA5 are activated and interact with their adaptor protein mitochondrial antiviral signaling (MAVS) to induce the RLR signaling pathway and subsequent type I IFN production [14,15][14][15]. Although both KSHV and EBV are DNA viruses, infection with these viruses has been reported to induce RLR signaling pathways because their infection leads to the production of virus- and host-derived RNAs with double-stranded structures, such as miRNAs, circular RNAs, and long noncoding RNAs. In addition to RLRs, KSHV and EBV infection can also be regulated by other RNA binding proteins involved in innate immunity, such as protein kinase R (PKR) and TLRs 3, 7 and 8 [12].

2. RIG-I-Like Receptors

2.1. Gammaherpesviruses Activate the RLR Signaling Pathway

RLRs are RNA sensors localized in the cytosol which include RIG-I, MDA5 and the laboratory of genetics and physiology (LGP2). All three RLRs share similar RNA binding domains, including the conserved DExD/H helicase domain and C-terminal domain (CTD) [16]. The N-termini of RIG-I and MDA5 have two additional tandemly linked caspase activation and recruitment domains (CARDs) that mediate the activation of adaptor protein MAVS [14,17,18][14][17][18]. Upon activation, MAVS recruits and activates downstream proteins, TNF receptor-associated factors (TRAFs), IκB kinase (IKK) and TANK-binding kinase 1 (TBK1). These subsequently activate transcription factors, nuclear factor-κB (NF-κB), interferon regulatory factor 3 (IRF3) and IRF7, which induce the expression of Type I IFN genes and proinflammatory cytokine genes (Figure 1) [14]. As LGP2 lacks the CARD domain, it does not directly activate MAVS and is considered a regulator of RIG-I and MDA5 [19]. Although RIG-I and MDA5 induce the same downstream signaling pathways upon RNA binding, they have distinct preferences for the RNA duplex structure they bind to. RIG-I recognizes dsRNA with a triphosphate group at its 5′ end (5′ppp) and RIG-I can also bind to long noncoding RNAs without these ends [20[20][21],21], while MDA5 senses long RNA duplexes (>4 kb) independent of 5′ppp [22].
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Figure 1. Gammaherpesviruses activate and evade the RNA-induced innate immune pathways. TLRs 3, 7, and 8 detect RNA in the endosome and RLRs (RIG-I and MDA5) detect dsRNA in the cytoplasm. During KSHV and EBV infection, TLRs 3, 7, and 8, and RLRs are activated by host or viral RNAs; activated TLR3 and TLR7/8 recruit and induce their downstream adaptor proteins TRIF and MyD88, respectively. Activated RLR induces the adaptor protein MAVS. These adaptor proteins subsequently recruit and induce common downstream proteins TNF receptor-associated factors (TRAFs) and TANK-binding kinase 1 (TBK1), leading to the phosphorylation and activation of the transcription factors interferon-regulatory factor 3 (IRF3), IRF7 and NF-κB that results in the production of type I interferons and other proinflammatory cytokines. Activation of TLR3 signaling induces KSHV RTA expression, which in turn promotes TRIF degradation. KSHV miRNA K5 blocks MyD88. KSHV ORF64, EBV BPLF1, and EBV miBART-3p inhibit RIG-I activation. EBV LMP1 reduces both RIG-I and MDA5 expression. KSHV vIRF1 inhibits the activation of RLRs’ adaptor protein, MAVS, and TLR3-mediated activation of IRF3. Upon binding to dsRNA, PKR undergoes autophosphorylation and becomes an activated kinase to phosphorylate a key translation initiation factor (eIF2α), inducing the shutdown of global protein synthesis and inhibiting cell growth. KSHV ORF57, EBV SM or EBV noncoding RNA EBERs interact with PKR and inhibit PKR activation. * EBER: the role of EBERs in PKR phosphorylation is unclear due to conflicting reports.
Both EBV and KSHV infections trigger the RLR signaling pathway through viral/ host RNA binding to the RNA sensors, RIG-I and MDA5. West et al. first reported that dsRNA is induced during KSHV lytic replication by demonstrating its accumulation in reactivating cells using a dsRNA-specific antibody J2 [23]. Further studies revealed the binding of multiple RNA transcript fragments induced by KSHV lytic reactivation to RIG-I, such as ORF2543561–43650, ORF810420–10496 and the repeat region LIR1119059–119204, through high-throughput sequencing of RNA isolated by the immunoprecipitation approach [24]. In addition to the recognition of KSHV viral dsRNA by RIG-I, many host RNAs have been identified to be bound to RIG-I and MDA5 during KSHV lytic reactivation [25]. Host vault RNAs (vtRNAs) are the most highly enriched RIG-I bound RNAs in KSHV-infected cells [25]. vtRNAs are expressed in unstressed cells in a non-immunostimulatory state as their 5′ppp ends are removed by the cellular dual specificity phosphatase 11 (DUSP11) [26,27][26][27]. However, KSHV lytic reactivation reduced the expression of DUSP11 and increased the RIG-I activating 5’ppp-vtRNAs [25]. Furthermore, depletion of RIG-I, MDA5 or their adapter MAVS individually enhances KSHV replication during viral lytic reactivation and primary infection [23[23][25],25], suggesting that the KSHV-induced RIG-I/MDA5-mediated RLR signaling pathway restricts viral infection. EBV-encoded RNA1 (EBER1) and EBER2 are small noncoding RNAs that are transcribed by host RNA polymerase III (Pol III) and are abundantly expressed in latent EBV-infected cells. In spite of EBER1 and EBER2 being short RNAs of 167 and 172 nucleotides, respectively, both have secondary structures consisting of intermolecular base-pairing and several stem-loops that can trigger RLR sensing [28,29][28][29]. EBERs are primarily found in the nucleus, although there is some evidence of their presence in the cytoplasm and their interaction with cytosolic proteins [30]. Inhibition of polymerase III activity suppresses the expression of EBERs and decreased EBER-induced type I interferon production [31]. EBERs are able to interact with RIG-I and activate RIG-I-mediated type I IFNs and ISGs production, and either EBER could trigger type I IFN responses independently [31,32][31][32]. EBERs also induce IL-10 production which is dependent on the activation of RIG-I where depletion of RIG-I or expression of RIG-I lacking in the CARD domain blocks EBER-induced IL-10 expression [33]. This indicates that EBERs are recognized by RIG-I and activate downstream signaling to induce type I IFN and other cytokines in EBV-infected cells, and this activity involves the CARD domain of RIG-I. Thus, EBV infection stimulates expression of immunostimulatory RNA substrates for dsRNA sensors that trigger type I IFN and cytokine production.

2.2. Gammaherpesvirues Evade the RLR Signaling Pathway by Utilizing Both Viral and Host Proteins

KSHV and EBV deploy multiple viral proteins to disrupt RLR activation during de novo infection and lytic reactivation in order to efficiently evade the antiviral response and establish their life cycle. The protein homologs BPLF1 and ORF64 are viral deubiquitinating enzymes (DUBs) of EBV and KSHV, respectively, that target the RLR sensor RIG-I [34,35,36][34][35][36]. RIG-I is subject to K63-polyubiquitination by ubiquitin ligases, including tripartite motif protein 25 (TRIM25), Riplet, Mex-RNA binding family member C (MEX3C), TRIM4 and TRIM21 [37,38][37][38]. This K63-polyubiquitination of the RIG-I CARD domain is essential for activating adaptor protein MAVS and recruiting downstream signaling molecules [37,39][37][39]. Both ORF64 and BPLF1 have been shown to decrease RIG-I ubiquitination, leading to reduced RIG-I activation and suppression of downstream innate immune responses [40,41][40][41]. EBV BPLF1 promotes the dimerization and autoubiquitination of TRIM25, which leads to impaired RIG-I ubiquitination [40]. KSHV also utilizes the viral interferon regulatory factor 1 (vIRF1) to target MAVS and block RLR signaling. vIRF1 is recruited to the mitochondria and inhibits MAVS aggregation during virus replication that in turn negatively regulates the MAVS-mediated antiviral responses and promotes KSHV replication [42]. Additionally EBV-encoded latent membrane protein 1 (LMP1) degrades RIG-I and MDA5 by recruiting E3 ubiquitin ligases to induce the proteasomal degradation of RIG-I and MDA5 [43]. Furthermore, EBV-encoded microRNA miBART6-3p targets the 3′ untranslated region (UTR) of the RIG-I mRNA, resulting in the decreased expression of RIG-I-induced interferon and interferon-stimulated genes (ISGs) [44]. In addition, since Pol-III-transcribed EBERs are able to activate the RIG-I sensing pathway as described above, the EBV lytic protein replication and transcription activator (Rta) interacts with Pol III to suppress the expression of EBERs and other immunogenic small RNAs [45]. Thus, gammaherpesviruses not only directly inhibit the activation of proteins involved in the RLR signaling pathway but also decrease the availability of RLR ligands induced during KSHV and EBV reactivation and replication. In addition to utilizing virus-derived proteins and noncoding RNAs, EBV and KSHV also hijack host proteins to evade the RLR signaling pathway. ADARs are RNA-editing enzymes that bind to dsRNA and convert adenosine to inosine in dsRNA. There are three members of the human ADAR family, designated ADAR1 (ADAR), ADAR2 (ADARB1), and ADAR3 (ADARB2), where ADAR1 is responsible for the majority of the A-to-I editing activity in mammalian cells [46]. Widespread A-to-I editing of both the host and viral transcripts has been observed in KSHV-infected cells, and the A-to-I editomes are further expanded during KSHV lytic reactivation [47]. The A-to-I editing of the induced dsRNAs by KSHV infection prevents them from being recognized and detected by RLRs within the cell. Thus, in the absence of ADAR1, these KSHV-induced dsRNAs lacking A-to-I editing are exposed to and recognized by MDA5/RIG-I to stimulate the RLR antiviral signaling pathway, leading to the increased induction of IFNs, and resulting in the inhibition of KSHV lytic replication [48]. A-to-I editing also affects latent EBV viral infection. EBV pri-miR-BART6, targeted by the Dicer enzyme of the mammalian RNA-induced silencing complex (mRISC), modulates the EBV latency state through the control of viral gene expression. A-to-I editing of pri-mi-BART6 suppresses its targeting by Dicer which leads to viral lifecycle transitions to either type III latency or lytic reactivation [49]. In addition to pri-mi-BART6, A-to-I editing has also been found in EBV pri-miR-BART3, pri-miR-BART8 and pri-miR-BART11, as well as the KSHV K12/Kaposin transcript [50,51][50][51]. Furthermore, EBV A-to-I hyperedited OriP transcripts can bind to ADAR1 and promote EBV viral lytic replication [52]. Hence, KSHV and EBV not only utilize their own proteins or RNAs, but also usurp cellular proteins to escape the innate immune response.

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