Proteomics

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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 (RCMV)-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 analyses and in vitro reconstitution 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 to displace them from DDB1. Moreover, structure analyses solved the mechanism of STAT2 recruitment, and indicate that E27-binding disturbs the formation of active STAT2 complexes by occupying the IRF9-binding interface. Our results provide first structural insights into the cytomegalovirus-encoded interferon antagonism and establish an atomic model for STAT2 counteraction by CRL4 misappropriation, with important implications for viral immune evasion.

ORGANISM(S): Cellular Organisms

SUBMITTER: Juri Rappsilber 

PROVIDER: PXD033366 | JPOST Repository | Thu Dec 15 00:00:00 GMT 2022

REPOSITORIES: jPOST

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Publications

Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve as common infection models. Here, we conducted global proteome profiling of rat CMV-infected cells and uncovered a pronounced loss of the transcription factor STAT2, which is crucial for antiviral interferon signalling. Via deletion mutagenesis, we found that the viral protein E27 is required for CMV-induced STAT2 depletion. Cellular and in vitro analyses showed that E27 e  ...[more]

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