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Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus

Henry Weisbach1, Christoph Schablowsky1, Barbara Vetter1

  • 1Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.

Plos Pathogens
|January 28, 2017
PubMed

Insights

Human cytomegalovirus (HCMV) uses pp150 to control cell cycle progression, preventing viral replication in S/G2 phases. This strategy, involving pp150 and pUL21a, is crucial for efficient HCMV infection.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Host-pathogen interactions involve a balance between host restriction factors and viral countermeasures.
  • Human cytomegalovirus (HCMV) exhibits complex regulation of its replication cycle.
  • Viral proteins can manipulate host cell processes to facilitate infection.

Purpose of the Study:

  • To investigate the role of the HCMV tegument protein pp150 in regulating the host cell cycle during productive infection.
  • To determine the physiological relevance of pp150's interaction with cyclin A in HCMV replication.
  • To elucidate the cooperative mechanism between pp150 and pUL21a in HCMV cell cycle manipulation.

Main Methods:

  • Employing a pp150 mutant virus deficient in cyclin A binding.
  • Analyzing the impact of viral gene expression on host cell cycle progression (G2/M arrest).
  • Assessing viral replication and cell viability in cells infected with wild-type and mutant HCMV strains.

Main Results:

  • Unrestricted viral gene expression in S/G2 phases led to G2/M arrest.
  • G2-arrested cells supported viral replication, while mitotic cells did not.
  • The viral protein pUL21a destabilized cyclin A, maintaining the G2-arrest.
  • Disabling both pp150 and pUL21a interactions with cyclin A resulted in mitotic entry, reduced cell viability, and impaired virus growth.

Conclusions:

  • HCMV pp150 restricts viral gene expression in S/G2 phases by binding to cyclin A.
  • HCMV employs a cell cycle synchronization strategy involving pp150 and pUL21a to target cyclin A.
  • This coordinated targeting and avoidance of cyclin A is essential for productive HCMV infection and optimal virus yield.

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