Artikel ; Online: Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor.
2023 Band 42, Heft 5, Seite(n) e112351
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 ... ...
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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Mesh-Begriff(e) | Animals ; Humans ; Mice ; Rats ; Cryoelectron Microscopy ; Cytomegalovirus Infections/genetics ; Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism ; Interferons/metabolism ; Muromegalovirus ; STAT2 Transcription Factor/genetics ; STAT2 Transcription Factor/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Receptors, Interleukin-17/metabolism |
Chemische Substanzen | 2,4-bis(N,N'-di(carboxymethyl)aminomethyl)fluorescein (3147-15-7) ; Interferon-Stimulated Gene Factor 3, gamma Subunit ; Interferons (9008-11-1) ; IRF9 protein, rat ; STAT2 protein, human ; STAT2 Transcription Factor ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Receptors, Interleukin-17 |
Sprache | Englisch |
Erscheinungsdatum | 2023-02-10 |
Erscheinungsland | England |
Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 586044-1 |
ISSN | 1460-2075 ; 0261-4189 |
ISSN (online) | 1460-2075 |
ISSN | 0261-4189 |
DOI | 10.15252/embj.2022112351 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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