Abstract
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.
Highlights
Control of the cell division cycle by cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs) is fundamental for proliferation, development and homeostasis of multicellular organisms [1, 2]
To ensure that viral replication is not disturbed by cell division, Human cytomegalovirus (HCMV) has developed a twofold strategy of cyclin A targeting and avoidance
HCMV employs the viral cyclin A substrate pp150 to synchronize the onset of replication with G1, a cell cycle phase of low cyclin A expression
Summary
Control of the cell division cycle by cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs) is fundamental for proliferation, development and homeostasis of multicellular organisms [1, 2]. To reprogram the cell cycle for their own benefit, viral pathogens have evolved, or acquired from their host, genes and sequence motifs facilitating direct interaction with the cyclin-CDK protein network [3]. The repertory of herpesviral cell cycle regulators comprises on the one hand factors leading to constitutive activation of the cell cycle. This is exemplified by the β and γ-herpesviral orthologs of cyclins [4] and CDKs [5], which release CDK substrate phosphorylation from the control of cellular cyclins and CKIs [6, 7]. Herpesviruses target cellular cyclin-CDK activity to arrest the cell cycle at stages conducive to virus replication [8]. In contrast to CKIs, pUL21a does not act as a stoichiometric inhibitor of cyclin-CDK complexes but recruits cyclin A ( referred to as cyclin A2) for proteasomal degradation [9, 10]
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