Structural basis for STAT2 suppression by flavivirus NS5

Abstract

Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy viruses use to establish infections, yet the detailed mechanism remains elusive due to lack of structural information of the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved inter-domain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the N-terminal domain of hSTAT2. Disruption of these ZIKV NS5–hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent condition. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.

The Molecular Interactions of ZIKV and DENV with the Type-I IFN Response

“…Finally, similar to ZIKV, DENV NS5 mediates human STAT2 degradation in a proteasome dependent manner [ 114 ]. This similarity is highlighted by a recent study that found the specific interacting residues of NS5 and its binding mode with human STAT2 were highly conserved between ZIKV and DENV [ 115 ]. However, in contrast to ZIKV this requires natural viral processing of NS5 from the polyprotein and is dependent on the ubiquitin ligase UBR4 [ 116 ].…”

Akt Interacts with Usutu Virus Polymerase, and Its Activity Modulates Viral Replication

“…Thus, the interaction of NS5 with cyclophilins and the corresponding inhibition by cyclosporins [ 43 ], Hsp70 [ 44 ], and with a great number of proteins related to the regulation of the immune system has been described [ 45 ]. In fact, most flavivirus NS5 interactions described so far are with proteins related to the interferon response [ 46 ], such as Hsp90 and JAK/STAT, among others [ 47 , 48 , 49 , 50 ]. It seems that the nuclear location of NS5 is not relevant to this type of modulation of the immune response [ 51 ].…”

A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses

“…STAT1 and 2 are central to IFN signalling and thus are common targets for viral antagonism (Harrison and Moseley, 2020), however structural details of STAT:antagonist complexes have remained elusive with a few exceptions. The complex of SeV C protein with the N-terminal domain of STAT1 indicates that C protein interferes with the oligomeric state of STAT1 (Oda et al, 2015) whilst the structures of dengue and Zika virus NS5 proteins in complex with STAT2 revealed that both NS5 proteins overlap the IRF9 binding site to prevent ISGF3 assembly (Wang et al, 2020). A similar mechanism was described for measles V protein (Nagano et al, 2020).…”