Identification of DNA-Damage DNA-Binding Protein 1 as a Conditional Essential Factor for Cytomegalovirus Replication in Interferon-γ-Stimulated Cells

PLoS Pathogens

Hartmut Hengel¹  Albert Zimmermann¹  Elke Bleifuß¹  Manuela Fiedler¹  Vu Thuy Khanh Le¹  Mirko Trilling¹ 

[1] Institute for Virology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

关键词: Immunoprecipitation;    Human cytomegalovirus;    Sequence motif analysis;    Interferons;    Antibodies;    Cytomegalovirus infection;    Small interfering RNAs;    Viral replication;   

DOI  :  10.1371/journal.ppat.1002069

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The mouse cytomegaloviral (MCMV) protein pM27 represents an indispensable factor for viral fitness in vivo selectively, antagonizing signal transducer and activator of transcription 2 (STAT2)-mediated interferon signal transduction. We wished to explore by which molecular mechanism pM27 accomplishes this effect. We demonstrate that pM27 is essential and sufficient to curtail the protein half-life of STAT2 molecules. Pharmacologic inhibition of the proteasome restored STAT2 amounts, leading to poly-ubiquitin-conjugated STAT2 forms. PM27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein, DNA-damage DNA-binding protein (DDB) 1. Truncation mutants of pM27 showed a strict correlation between DDB1 interaction and their ability to degrade STAT2. SiRNA-mediated knock-down of DDB1 restored STAT2 in the presence of pM27 and strongly impaired viral replication in interferon conditioned cells, thus phenocopying the growth attenuation of M27-deficient virus. In a constructive process, pM27 recruits DDB1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the STAT2-dependent antiviral state of cells to permit viral replication.

【 授权许可】

CC BY