AI Article Synopsis

  • Human cytomegalovirus (CMV) disrupts the antiviral response by depleting the STAT2 transcription factor, which is essential for signaling against viral infections.
  • This depletion is mediated by the viral protein E27, which triggers the degradation of STAT2 using cellular mechanisms that involve ubiquitin ligase complexes.
  • Structural analyses reveal how E27 mimics host proteins to effectively recruit and degrade STAT2, highlighting a conserved strategy for immune evasion in both rat and mouse models of CMV infection.

Article Abstract

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 exploits host-cell Cullin4-RING ubiquitin ligase (CRL4) complexes to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopy revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors called DCAFs (DDB1- and Cullin4-associated factors), thereby displacing them from the catalytic core of CRL4. Moreover, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, which partially overlaps with the IRF9 binding site. Structure-based mutations in M27, the murine CMV homologue of E27, impair the interferon-suppressing capacity and virus replication in mouse models, supporting the conserved importance of DCAF mimicry for CMV immune evasion.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9975947PMC
http://dx.doi.org/10.15252/embj.2022112351DOI Listing

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