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Master mitotic kinases regulate viral genome delivery during papillomavirus cell entry

Matteo Rizzato1, Fuxiang Mao1, Florian Chardon1

  • 1Institute of Cellular Virology, Westphalian Wilhelms-University of Münster, Münster, Germany.

Nature Communications
|January 22, 2023
PubMed

Insights

Mitotic kinases CDK1 and PLK1 phosphorylate human papillomavirus (HPV) minor capsid protein L2, enabling viral DNA delivery to mitotic chromosomes. This phosphorylation regulates pathogen import into the nucleus during cell division.

Area of Science:

  • Cell Biology
  • Virology
  • Molecular Biology

Background:

  • Mitosis involves significant cellular rearrangements, including nuclear envelope breakdown.
  • Nuclear entry of human papillomavirus (HPV) genomes utilizes mitosis, with the L2 protein tethering viral DNA to mitotic chromosomes.
  • The precise mechanisms and regulatory factors governing HPV genome delivery to chromosomes during mitosis remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms of HPV genome tethering to mitotic chromosomes.
  • To identify cellular proteins and regulatory processes involved in HPV nuclear import during mitosis.
  • To investigate the role of L2 protein modifications during mitosis.

Main Methods:

  • Phosphorylation site analysis of HPV minor capsid protein L2.
  • In vitro kinase assays using CDK1 and PLK1.
  • Chromatin binding assays to assess L2-chromosome interactions.

Main Results:

  • Identified specific phosphorylation sites on L2 crucial for mitosis.
  • Demonstrated sequential phosphorylation of L2's chromosome binding region (CBR) by CDK1 and PLK1.
  • Showed that L2 phosphorylation regulates the timely delivery of HPV viral DNA (vDNA) to mitotic chromatin.

Conclusions:

  • Mitotic kinases CDK1 and PLK1 play a critical role in regulating HPV L2 phosphorylation.
  • L2 phosphorylation is essential for the efficient tethering of viral DNA to mitotic chromosomes.
  • This study provides key insights into the molecular mechanisms of nuclear import of viral DNA during mitosis.

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