Cooperative Roles of Fish PKZ and PKR in IFN Mediated Antiviral Response

In mammals, four members of eukaryotic initiation factor 2a(eIF2a) kinase family have been characterized, including double-stranded RNA (dsRNA)-dependent protein kinase (PKR), PKR-like endoplasmic reticulum (ER) eIF2a kinase (PERK), general control of nitrogen metabolism kinase 2 (GCN2), and heme regulated eIF2a kinase (HRI), which respond to various cellular stresses, respectively. Once upon virus infection, PKR is activated and subsequently phosphorylates eIF2a shut down protein synthesis, thus inhibiting viral replication.  

In fish, the first cloned eIF2a kinase gene is a novel gene PKR-like/PKZ rather than PKR (Fish Shellfish Immunol, 2004,17:353-366), which was performed by the Research Group of Fish Developmental Genetics and Cell Engineering (Principal Investigator: Prof. GUI Jianfang) at Institute of Hydrobiology, Chinese Academy of Sciences (IHB). In 2008, this group also confirmed the existence of PKR gene in fish (J Virol, 2008, 82:6889-6901).  

Recently, they found that PKR and the fish-specific gene PKZ are typical interferon (IFN)-inducible eIF2a kinases, which are tandemly arranged in crucian carp genome and cooperatively inhibit virus replication via phosphorylating eIF2a. Distinct from mammalian PKRs, fish PKZ and PKR display an ability to phosphorylate eIF2a under the condition of IFN treatment. Although the underlying mechanism remains to be established, fish PKZ and PKR might form homodimers rather than heterodimers to phosphorylate eIF2a blocking virus raplication.  

These results together suggest that fish PKZ is a novel vertebrate eIF2a, and that the coexistence of PKZ and PKR in fish genome is to play a cooperative role in response to virus invasion. In addition, like PKR that is a sensor specific to dsRNA, fish PKZ might be a potential sensor protein to recognize Z-DNA/Z-RNA because PKZ is the third Z-DNA binding domain-containing protein found in vertebrates. 

This work was supported by grants from the 973 National Basic Research Program of China. The research was fulfilled by IHB Ph. D student LIU Tingkai et al. under the supervision of Profs. ZHANG Yibing and GUI Jianfang. The related article was published online in Journal of Virology, 2011, 85(23):12769-12780. (