Structure and mechanism of a novel cytomegaloviral DCAF mediating interferon antagonism

Abstract

Human cytomegalovirus (CMV) is a highly relevant pathogen, and its rodent counterparts serve as common infection models. Global proteome profiling of rat CMV-infected cells uncovered a pronounced loss of the transcription factor STAT2, which is crucial for interferon signalling. Deletion mutagenesis documented that STAT2 is targeted by the viral protein E27. Cellular and in vitro analyses showed that E27 exploits host-derived Cullin4-RING ubiquitin ligases (CRL4) to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopic structure determination revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors (DDB1- and Cullin4-associated factors, DCAFs) to displace them from the CRL4 catalytic core. Moreover, structural analyses elucidated the mechanism of STAT2 recruitment and indicate that E27-binding additionally disturbs STAT2 activation by occupying the IRF9 binding interface. For the first time, these data provide structural insights into cytomegalovirus-encoded interferon antagonism and establish an atomic model for STAT2 counteraction by CRL4 misappropriation with important implications for viral immune evasion.