Weisbach Henry, Schablowsky Christoph, Vetter Barbara, Gruska Iris, Hagemeier Christian, Wiebusch Lüder
Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
PLoS Pathog. 2017 Jan 27;13(1):e1006193. doi: 10.1371/journal.ppat.1006193. eCollection 2017 Jan.
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.
一般来说，宿主限制因子与病毒应对措施之间的拮抗作用决定了细胞对病毒感染的易感性或抗性。人类巨细胞病毒（HCMV）通过病毒被膜蛋白pp150进化出了一种额外的自我限制机制。根据一个细胞周期蛋白A结合基序，pp150可防止在原本完全允许感染的细胞的S/G2细胞周期阶段开始病毒基因表达。在这里，我们通过使用一种细胞周期蛋白A结合缺陷型pp150突变病毒，探讨了这种限制在HCMV有效感染过程中的生理相关性。在S/G2期不受限制的病毒基因表达的一个后果是诱导G2/M期阻滞。被阻滞在G2期而非有丝分裂期的细胞支持病毒复制。病毒基因产物pUL21a使细胞周期蛋白A不稳定是维持病毒允许的G2期阻滞所必需的。一种HCMV双点突变体，其中pp150和pUL21a在与细胞周期蛋白A的相互作用中均被破坏，导致大多数受感染细胞进入有丝分裂，对细胞活力和病毒生长产生严重负面影响。因此，pp150和pUL21a在功能上相互协作，共同构建了一种针对细胞周期蛋白A的靶向和规避的细胞周期同步策略，这对于HCMV的有效感染至关重要。
