Structural basis for the regulatory function of a complex zinc-binding domain in a replicative arterivirus helicase resembling a nonsense-mediated mRNA decay helicase

Deng, Zengqin; Lehmann, Kathleen C.; Li, Xiaorong; Feng, Chong; Wang, Guoqiang; Zhang, Qi; Qi, Xiaoxuan; Yu, Lin; Zhang, Xingliang; Feng, Wenhai; Wu, Wei; Gong, Peng; Tao, Ye; Posthuma, Clara C.; Snijder, Eric J.; Gorbalenya, Alexander E.; Chen, Zhongzhou

Nidoviruses constitute an order of +RNA viruses composed of virus groups targeting a wide variety of mammalian, avian and invertebrate hosts. In mammals, nidovirus infection can be associated with severe respiratory disease, as in the case of porcine reproductive and respiratory syndrome (PRRS) (16) , one of the leading swine diseases (caused by arteriviruses), and zoonotic coronavirus infections in humans, like severe acute respiratory syndrome (17) and Middle East respiratory syndrome (18) . The continuing outbreak of the latter disease is currently attracting worldwide attention, in particular because of its $40% case fatality rate. Besides their pathogenic properties, nidoviruses have been studied for their extraordinarily large RNA genomes: even the shortest nidovirus genome (the 12.7-kb RNA of the arterivirus equine arteritis virus, EAV) outranks almost all other mammalian +RNA virus genomes, whereas coronavirus genomes (26.3-31.7 kb) are larger than those of any other RNA virus group. Their large genome size enabled nidoviruses to evolve substantial genetic complexity, which is evident from (among other properties) the acquisition of a variety of enzymatic activities and accessory proteins, many of which are lacking or rare in other +RNA viruses (19) . These proteins appear to contribute to the regulation of the complex RNA synthesis of nidoviruses, which occurs exclusively in the cytoplasm of the infected cell, and to the elaborate array of virus-host interactions needed to support efficient virus replication (13, 20) . For example, nidoviruses with genomes >20 kb use a proofreading 3 0 -5 0 RNA exonuclease that is proposed to promote the fidelity of viral RNA synthesis (19, (21) (22) (23) (24) (25) (26) (27) . However, it is completely unknown whether and how nidoviruses deal with translational quality control during the expression of their large multicistronic genomic RNAs, which also serve as mRNAs for the synthesis of the viral replicative enzymes.