Cellular RNA is usually unable to activate the immune response, with several modifications protecting self-RNA from being recognized by pattern recognition receptors in the cytoplasm, under the normal conditions described. Recent studies have revealed that discriminating between self and non-self RNA depends on the 5′ end of the molecule. n the nucleus, RNA polymerases synthesize nascent transcripts possessing a 5′ triphosphate group (ppp-RNA) at the 5′ end. In the case of premature mRNA, 5′ ends of nascent transcripts undergo co-transcriptional modification – the addition of a cap structure, meaning N7-methylated guanosine is joined to the first transcribed nucleotide through a 5′-5′ triphosphate bridge, forming a cap-0 structure.
MDA5: Similarly to RIG-I, MDA5, the second member of the RLR family, is composed of CARD, CTD, and helicase domains. However, in contrast to RIG-I, MDA5 does not recognize specific chemical groups at the 5′ end of RNA, rather discriminating for dsRNA based on molecular length.
LGP2: Another RLR family member, LGP2, was originally found as a highly expressed gene in mammary tumours.
IFITs: Among ISGs, the most important contributors to facilitating the immune response to exogenous RNA are IFITs. The human genome encodes five different IFIT proteins, namely IFIT1, IFIT1B, IFIT2, IFIT3, and IFIT5. Although IFITs, in contrast to RLRs, recognize ssRNA and bind directly to non-self RNA to inhibit their translation or replication, only IFIT1 and IFIT5 are able to interact directly with RNA 5′ end. IFIT1 and IFIT5 discriminate RNA on the basis of the 5′ end of the transcript, with IFIT5 binding only ssRNAs with a triphosphate group at this position, while ligands of IFIT1 may possess a triphosphate group or a cap-0.
Nucleotide Oligomerization and binding Domain (NOD)-like receptor (NLRs) are a large family of pattern recognition receptors responsible for immune system activation during microbial infection, cellular injury or stress. NLR members share common structural features, they all are composed of N-terminal effector, central nucleotide binding domain (NBD) and C-terminal leucine-rich repeat (LRR) domain.
NLRs are important in the innate immune response to viral infection.
–NOD-like receptor NOD2: is a cytosolic innate pattern recognition receptor that recognizes the muramyl dipeptide fragment of peptidoglycan present in bacterial cell walls. Stimulation of NOD2 results in signaling through the adapter protein receptor interaction protein kinase 2 (RIP2) to activate NF-kB and mitogen activated protein kinases. In addiiton to its role in innate immunity to bacterial infection, it is also required for the efficient induction of both B and T cells response.
Protein Kinase R (PKR): is also one of the sensors of viral invasion. PKR is a cytosolic protein composed of dsRNA bindign motifs and a serine/threonine kianse domain. Binding of PKR with viral dsRNA resutls in the phosphorylation of the translation initiation factor, eIF2?, and translational inhibition. In addition, production of type I IFNs by dsRNA is possibly regulated by PKR.
RIG-I(retinoic-acid inducible gene-I): can recognize viral dsRNA to induce the type I IFN response in vitro. RIG-I contains an N-terminal caspase recruitment domain (CARD) and a C-terminal DExD/H box RNA helicase domain. The helicase domain is responsible for dsRNA recognition, and the CARD domain activates downstream signaling pathways.
RIG-I, but not the TLR system plays an essential role in antiviral responses in various cells except pDCs. Reciprocally, the TLR system, but not RIG-I, is indispensable to IFN-? secretion in pDCs.
RIG-I, with a multi-domain structure typical for proteins from the RLR group, is the first known member of the RLR family. RIG-I is composed of N- and C-terminal domains, with its central part known as a core.
TLRs are critical for the recongition of pathogen-specific molecular patterns (PAMPs) derived from viral species. Among 11 reported TLRs, TLR3, TLR4, TLR7, TLR8, and TLR9 are involved int he recognition of viral components.
TLRs are transmembrane glycoprotein receptors with an extracellular N-terminal part, responsible for PAMP-binding, and an intracellular C-terminal region, also known as a Toll/IL-1 R homology (TIR) domain, which takes part in downstream signalling. Characteristic features of this membrane-anchored receptor family include multiple leucine-rich repeats (LRRs), which form a horseshoe structure in the extracellular ectodomain, similarity in the TLR C-terminal region to the intracellular domain of the interleukin-1 receptor (IL-1 R). In humans, this family consists of 10 members, of which four, TLR3, 7, 8, and 9, are responsible for sensing foreign nucleic acids. Sequence homology has revealed that TLR7, TLR8, and TLR9 exist in one evolutionarily conserved cluster within the TLR family. TLR9 recognizes unmethylated deoxycytidyl-phosphate-deoxyguanosine (CpG) motifs commonly present in bacterial and viral genomes, whereas TLR3 and TLR7 and 8 sense ds- and ssRNAs, respectively.