Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus

PLoS Pathogens

Christian Hagemeier¹  Barbara Vetter¹  Henry Weisbach¹  Christoph Schablowsky¹  Iris Gruska¹  Lüder Wiebusch¹ 

[1] Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany

关键词: Cyclins;    Cell cycle;    cell division;    Viral replication;    Synthesis phase;    Flow cytometry;    Human cytomegalovirus;    Cloning;    Viral gene expression;   

DOI  :  10.1371/journal.ppat.1006193

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Generally, the antagonism between host restriction factors and viral countermeasures decides on cellular permissiveness or resistance to virus infection. Human cytomegalovirus (HCMV) has evolved an additional level of self-imposed restriction by the viral tegument protein pp150. Depending on a cyclin A-binding motif, pp150 prevents the onset of viral gene expression in the S/G2 cell cycle phase of otherwise fully permissive cells. Here we address the physiological relevance of this restriction during productive HCMV infection by employing a cyclin A-binding deficient pp150 mutant virus. One consequence of unrestricted viral gene expression in S/G2 was the induction of a G2/M arrest. G2-arrested but not mitotic cells supported viral replication. Cyclin A destabilization by the viral gene product pUL21a was required to maintain the virus-permissive G2-arrest. An HCMV double-point mutant where both pp150 and pUL21a are disabled in cyclin A interaction forced mitotic entry of the majority of infected cells, with a severe negative impact on cell viability and virus growth. Thus, pp150 and pUL21a functionally cooperate, together building a cell cycle synchronization strategy of cyclin A targeting and avoidance that is essential for productive HCMV infection.

【 授权许可】

CC BY