The SARS-Unique Domain (SUD) of SARS Coronavirus Contains Two Macrodomains That Bind G-Quadruplexes

Tan, Jinzhi; Vonrhein, Clemens; Smart, Oliver S.; Bricogne, Gerard; Bollati, Michela; Kusov, Yuri; Hansen, Guido; Mesters, Jeroen R.; Schmidt, Christian L.; Hilgenfeld, Rolf

PARP-1 and most of its family members are located to the nucleus, while PARP-4 and others predominantly act in the cytoplasm [50] [51] [52] . PARP-4 is incorporated into vaults, RNAcontaining subcellular particles in the cytoplasm [55] . Furthermore, ZAP, a human antiviral protein comprising a C-terminal PARP-like domain devoid of catalytic activity, has been shown to exhibit antiviral activity on alphaviruses [56] , which contain an Xdomain similar to that of coronaviruses [23, 27, 28] . In addition, ZAP contains an N-terminal zinc-finger domain, a central TiPARP (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible PARP) domain, and a WWE domain (a protein-protein interaction module in ubiquitin and ADP-ribose conjugation proteins). In fact, ZAP appears to be part of the human innate immune system and to play a role comparable to APOBEC3G in HIV infection [57] . It is possible that this group of viruses has evolved macrodomains to counteract the antiviral activity of ZAP. Indeed, macrodomains can inhibit PARPs, as has been shown for the macrodomain of the histone mH2A1.1, which downregulates the catalytic activity of PARP-1 [58] . Having three macrodomains at its disposal, SARS-CoV may be much more efficient in knocking down the antiviral response of the host cell than other coronaviruses. Whether this involves a direct interaction between SUD and ZAP or another member of the PARP family, or competition for G-quadruplexes in viral or host-cell RNA, remains to be shown.