Inhibitors

Both viral as well as cellular inhibitors have been identified. The observation that cellular RNA can trigger PKR activation necessitates a mechanism whereby the cell can limit inappropriate activation of the kinase. Accordingly, a number of cellular proteins, such as the ribosomal protein L18 and the eIF2a-associated glycoprotein p67, have been shown to repress PKR (Kumar et al. 1999; Gil et al. 2000b). Additional cellular repressors include nucleophosmin, which is overex-pressed in a variety of human malignancies, and the oncolytic TRBP, as discussed above (Park et al. 1994; Pang et al. 2003). Three additional proteins, C114, HSP90 and P58IPK, with common protein-protein interacting motifs, one with the RBMs conserved in PKR and two with tetratricopeptide repeats, associate with and inhibit PKR (Melville et al. 1997; Donze et al. 2001; Yin et al. 2003). C114 is induced by interleukin-11 and is an example of a gp130 family cytokine modulator of PKR function (Yin et al. 2003). The Fanconi anaemia (FA) proteins, which regulate chromosome stability, reportedly associate with PKR to control its activity (Gunnery and Mathews 1998).

To circumvent the antiviral effects of IFN and to reduce an inflammatory reaction mediated by PKR, viruses have evolved elaborate mechanisms to inhibit PKR (Table 1). These include the synthesis of inhibitory dsRNAs, such as the internal ribosomal entry site from the hepatitis C virus, and the noncod-ing EBER-1 and -2 from the Epstein-Barr virus, as well as the adenoviral VAI RNA (Galabru et al. 1989; Sharp et al. 1993; Vyas et al. 2003). A wide variety of viral proteins inhibit PKR indirectly by sequester activating dsRNA. Examples include the reovirus sigma3 protein and the vaccinia viral E3L gene product (Davies et al. 1993; Yue and Shatkin 1997). Other proteins such as Us11 from the Herpes simplex virus and MC159L from the Molluscum contagiosum virus inhibit PKR indirectly (Poppers et al. 2000; Gil et al. 2001). At least one of these (Us11) does so by inhibiting PACT (Peters et al. 2002). The influenza virus recruits the cellular inhibitor P58IPK (Lee et al. 1994; Gale et al. 1996, 1998; Tan et al. 1998). Similarly, the Herpes simplex virus y1 34.5 recruits the catalytic subunit of protein phosphatase 1a to dephosphorylate PKR (Chou et al. 1995). The poxvirus caspase-8 inhibitor, CrmA, inhibits PKR-mediated apoptosis (Ezelle et al. 2001). Other viral proteins, such as NS5A from the hepatitis C viral, vIRF-2 from Herpes simplex viral, vaccinias E3L and influenza NS1 proteins directly interact to inhibit PKR (Gale et al. 1997; Sharp et al. 1998; Tan and Katze 1998; Burysek and Pitha 2001). Still other inhibitors, such as the HIV TAT, vaccinia K3L and hepatitis D virus small delta antigen (S-HDAg), interact with PKR as substrates. In the instance of K3L from vaccinia virus, or C8L from swinepox virus, the proteins bind directly to PKR to block the substrate interaction sites (Carroll et al. 1993; Davies et al. 1993; Kawagishi-Kobayashi et al. 1997, 2000).

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