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Review
. 2013 Jun;70(11):1949-63.
doi: 10.1007/s00018-012-1149-4. Epub 2012 Sep 9.

Multi-level regulation of cellular recognition of viral dsRNA

Alys Peisley  1 , Sun Hur
Affiliations
Review

Multi-level regulation of cellular recognition of viral dsRNA

Alys Peisley et al. Cell Mol Life Sci. 2013 Jun.

Abstract

Effective antiviral immunity depends on accurate recognition of viral RNAs by the innate immune system. Double-stranded RNA (dsRNA) often accumulates in virally infected cells and was initially considered a unique viral signature that was sufficient to initiate antiviral response through dsRNA receptors and dsRNA-dependent effectors such as Toll-like receptor 3, retinoic acid inducible gene-1, protein kinase RNA-activated and oligoadenylate synthetase. However, dsRNA is also present in many cellular RNAs, raising a question of how these receptors and effectors discriminate between viral and cellular dsRNAs. Accumulating evidence suggests that innate immune sensors detect not only dsRNA structure but also other and often multiple features of RNA such as length, sequence, cellular location, post-transcriptional processing and modification, which are divergent between viral and cellular RNAs. This review summarizes recent findings on the substrate specificities of a few selected dsRNA-dependent effectors and receptors, which have revealed more complex mechanisms involved in cellular discrimination between self and non-self RNA.

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Figures

Fig. 1
Fig. 1
Schematic diagram of cellular responses to viral dsRNA. Upon viral infection, viral dsRNA is recognized by pattern recognition receptors (PRRs) such as RIG-I, MDA5, and TLR3, which stimulate expression of type I interferons (e.g., IFNα/β) via IRF3/7 or NF-κB pathways. Expressed IFNα/β cytokines are secreted into the extracellular space and stimulate interferon receptors in an auto or paracrine manner, which in turn activates the JAK/STAT signaling pathway to up-regulate expression of interferon-stimulated genes (ISGs). ISGs include PRRs such as RIG-I and MDA5, as well as antiviral effector proteins such as OAS and PKR, which suppress global protein synthesis and establish the antiviral state
Fig. 2
Fig. 2
a Schematic of dsRNA-dependent effector functions of PKR. b Structure of ribonuclease III dsRBD in complex with dsRNA (PDB: 2EZ6) [34]. No structure is currently available for PKR dsRBD in complex with dsRNA. Protein residues interacting with dsRNA are colored blue for basic residues and red for acidic residues. The minor and major grooves are indicated by m and M, respectively. c Summary of PKR-stimulatory and suppressive features of RNA
Fig. 3
Fig. 3
a Schematic of dsRNA-dependent effector functions of ADAR. b Summary of RNA specificity of ADAR. Examples of site-specific editing targets include the Q/R and R/G sites of GluR-B pre-mRNA. c Structure of ADAR2 dsRBDs in complex with a RNA stem-loop containing the R/G editing site of the GluR-2 pre-mRNA (PDB: 2L3J [73]). Protein residues interacting with dsRNA are shown in a stick representation and the flexible linker connecting between the two dsRBDs is represented by a dotted line. The minor and major grooves are indicated by m and M, respectively
Fig. 4
Fig. 4
a Schematic of dsRNA-dependent effector functions of OAS. Active states of OAS and RNase-L are indicated by an asterisk. The precise molecular nature of their active states is as yet unclear. b Structure of OAS free of dsRNA or ATP (PDB: 1PX5 [87]) in two opposite views. No structure is available in complex with ATP or dsRNA. Protein residues proposed to interact with the donor ATP molecule and dsRNA are shown as red sticks and yellow spheres, respectively. c Summary of RNA specificity of OAS. ‘W’ stands for A or U
Fig. 5
Fig. 5
a Schematic of dsRNA recognition and antiviral signal activation by TLR3. b Structure of TLR3 bound to dsRNA (PDB: 3CIY [109]) with a schematic depiction of the cytoplasmic TIR domain across the endosomal membrane. The minor and major grooves are indicated by m and M, respectively. c Summary of TLR3-stimulatory and suppressive features of RNA
Fig. 6
Fig. 6
a Schematic of dsRNA recognition and antiviral signal activation by RIG-I. b Summary of RIG-I-stimulatory and suppressive features of RNA. c Structure of RIG-I CTD in complex with dsRNA containing the 5′ triphosphate group (5′ppp) and blunt end (PDB: 3LRR [137]). The nucleotide at the 5′ end (green) is bound by positively charged residues (blue) in the 5′ppp binding pocket. d Structure of RIG-I before and after dsRNA binding (PDB: 4A2W [141] and 3TMI [139], respectively). Dotted lines and ovals indicate flexible linkers and disordered domains, respectively, which are not represented in the crystal structure
Fig. 7
Fig. 7
a Schematic of RNA recognition and antiviral signal activation by MDA5. b Electron micrograph and 2D-averaged image of the MDA5 filament formed on 512 and 112 bp dsRNA, respectively [146]. c Proposed model of dsRNA length-dependent signaling by MDA5. Filaments formed on short dsRNA disassemble rapidly during ATP hydrolysis, while filaments on longer dsRNA can undergo continuous cycles of filament assembly and disassembly, during which it activates the downstream antiviral signaling pathway through MAVS. d Summary of MDA5-stimulatory and suppressive features of RNA
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