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Review
. 2011 Oct;23(5):573-82.
doi: 10.1016/j.coi.2011.08.009. Epub 2011 Sep 15.

Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response

Christian K Pfaller  1 , Zhiqun Li, Cyril X George, Charles E Samuel
Affiliations
Review

Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response

Christian K Pfaller et al. Curr Opin Immunol. 2011 Oct.

Abstract

Double-stranded RNA (dsRNA) plays a centrally important role in antiviral innate immunity, both for the production of interferon (IFN) and also in the actions of IFN. Among the IFN-inducible gene products are the protein kinase regulated by RNA (PKR) and the adenosine deaminase acting on RNA 1 (ADAR1). PKR is an established key player in the antiviral actions of IFN, through dsRNA-dependent activation and subsequent phosphorylation of protein synthesis initiation factor eIF2α thereby altering the translational pattern in cells. In addition, PKR plays an important role as a positive effector that amplifies the production of IFN. ADAR1 catalyzes the deamination of adenosine (A) in RNA with double-stranded (ds) character, leading to the destabilization of RNA duplex structures and genetic recoding. By contrast to the antiviral and proapoptotic functions associated with PKR, the actions of ADAR1 in some instances are proviral and cell protective as ADAR1 functions as a suppressor of dsRNA-mediated antiviral responses including activation of PKR and interferon regulatory factor 3.

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Figures

Figure 1
Figure 1. Signaling pathways involved in the induction and action of interferon
(left) Nucleic acid sensors that respond to viral infection detect viral nucleic acids as foreign, thereby leading to the production and action of IFN. Sensors include the RIG-I and MDA5 cytosolic helicases and their mitochondrial membrane-associated adaptor IPS-1; the Toll-like receptor TLR3 that acts through the TRIF adaptor; TLRs 7, 8 and 9 that act through the MyD88 adaptor; and, RNA polymerase III that acts through IPS-1. RIG-I, MDA5 and TLR3 sense dsRNA, and pol III senses cytosolic dsDNA to produce dsRNA. TLRs 7 and 8 sense ssRNA, and TLR9 CpG-rich DNA. These nucleic acid sensors trigger antiviral innate immunity through activation of factors that lead to transcriptional activation of IFN production. (right) Signaling by types I, II and III interferons through the canonical JAK-STAT pathway is illustrated, leading to the transcriptional activation of IFN-stimulated genes. Among the IFN-induced gene products are ADAR1 and PKR, both of which bind dsRNA and possess enzymatic activity, one (PKR) regulated by dsRNA and the other (ADAR1) utilizing dsRNA as a substrate. Adapted from Samuel [26].
Figure 2
Figure 2. Domain organization of ADAR1 and PKR proteins from human cells and the enzymatic reactions catalyzed by them
(A) Domains. Alternative promoters and alternative splicing give rise to two size isoforms of ADAR1, an IFN-inducible p150 protein and a constitutively expressed p110 protein. A single-sized form of PKR is known that is inducible by IFN. The N-terminal regions of ADAR1 and PKR include repeated nucleic acid binding domains and the C-terminal regions the catalytic domains responsible for their enzymatic activities. Multiple dsRNA binding domains (RI, RII, RIII), three present in both ADAR1 p110 and p150 and two in PKR, are shown in red. RNA adenosine deaminase and protein kinase catalytic domains are shown in yellow for ADAR1 and PKR, respectively. The N-terminal region of the p150 form of ADAR1 also possesses two Z-DNA binding domains (Zα and Zβ, and p110 the Zβ copy, as shown in pink. (B) dsRNA is the substrate of ADAR1. ADAR1 p110 and p150 catalyze the C-6 deamination of adenosine (A) to yield inosine (I) in RNA with double-stranded character. (C) dsRNA is an effector of PKR. RNA-dependent activation of eIF2α protein kinase activity is mediated by autophosphorylation (green P) of PKR; phosphorylation of serine 51 (red P) of eIF2α by PKR leads to an inhibition of protein synthesis.
Figure 2
Figure 2. Domain organization of ADAR1 and PKR proteins from human cells and the enzymatic reactions catalyzed by them
(A) Domains. Alternative promoters and alternative splicing give rise to two size isoforms of ADAR1, an IFN-inducible p150 protein and a constitutively expressed p110 protein. A single-sized form of PKR is known that is inducible by IFN. The N-terminal regions of ADAR1 and PKR include repeated nucleic acid binding domains and the C-terminal regions the catalytic domains responsible for their enzymatic activities. Multiple dsRNA binding domains (RI, RII, RIII), three present in both ADAR1 p110 and p150 and two in PKR, are shown in red. RNA adenosine deaminase and protein kinase catalytic domains are shown in yellow for ADAR1 and PKR, respectively. The N-terminal region of the p150 form of ADAR1 also possesses two Z-DNA binding domains (Zα and Zβ, and p110 the Zβ copy, as shown in pink. (B) dsRNA is the substrate of ADAR1. ADAR1 p110 and p150 catalyze the C-6 deamination of adenosine (A) to yield inosine (I) in RNA with double-stranded character. (C) dsRNA is an effector of PKR. RNA-dependent activation of eIF2α protein kinase activity is mediated by autophosphorylation (green P) of PKR; phosphorylation of serine 51 (red P) of eIF2α by PKR leads to an inhibition of protein synthesis.
Figure 2
Figure 2. Domain organization of ADAR1 and PKR proteins from human cells and the enzymatic reactions catalyzed by them
(A) Domains. Alternative promoters and alternative splicing give rise to two size isoforms of ADAR1, an IFN-inducible p150 protein and a constitutively expressed p110 protein. A single-sized form of PKR is known that is inducible by IFN. The N-terminal regions of ADAR1 and PKR include repeated nucleic acid binding domains and the C-terminal regions the catalytic domains responsible for their enzymatic activities. Multiple dsRNA binding domains (RI, RII, RIII), three present in both ADAR1 p110 and p150 and two in PKR, are shown in red. RNA adenosine deaminase and protein kinase catalytic domains are shown in yellow for ADAR1 and PKR, respectively. The N-terminal region of the p150 form of ADAR1 also possesses two Z-DNA binding domains (Zα and Zβ, and p110 the Zβ copy, as shown in pink. (B) dsRNA is the substrate of ADAR1. ADAR1 p110 and p150 catalyze the C-6 deamination of adenosine (A) to yield inosine (I) in RNA with double-stranded character. (C) dsRNA is an effector of PKR. RNA-dependent activation of eIF2α protein kinase activity is mediated by autophosphorylation (green P) of PKR; phosphorylation of serine 51 (red P) of eIF2α by PKR leads to an inhibition of protein synthesis.
Figure 3
Figure 3. Modulation of innate immune responses mediated by the relative balance between ADAR and PKR acting as RNA sensors
Deamination of adenosine (A) to produce inosine (I) in duplex RNA structures catalyzed by ADAR leads to the nucleotide substitution of an I for an A in RNA. Because I base pairs with C instead of U, dsRNA with I:U mismatch base-pairs are less stable than A:U pairs. ADAR and PKR may also compete for dsRNA. ADAR, and A-to-I editing, may affect gene expression and function in virus-infected cells by a number of mechanisms including suppression of PKR and IRF3 activation.
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