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Ubiquitin proteolysis of a CDK-related kinase regulates titan cell formation and virulence in the fungal pathogen Cryptococcus neoformans

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  • Chengjun Cao

    (Rutgers University)

  • Keyi Wang

    (Rutgers University)

  • Yina Wang

    (Rutgers University)

  • Tong-Bao Liu

    (Rutgers University
    Southwest University)

  • Amariliz Rivera

    (Rutgers University)

  • Chaoyang Xue

    (Rutgers University
    Rutgers University
    Rutgers University)

Abstract

Fungal pathogens often undergo morphological switches, including cell size changes, to adapt to the host environment and cause disease. The pathogenic yeast Cryptococcus neoformans forms so-called ‘titan cells’ during infection. Titan cells are large, polyploid, display alterations in cell wall and capsule, and are more resistant to phagocytosis and various types of stress. Titan cell formation is regulated by the cAMP/PKA signal pathway, which is stimulated by the protein Gpa1. Here, we show that Gpa1 is activated through phosphorylation by a CDK-related kinase (Crk1), which is targeted for degradation by an E3 ubiquitin ligase (Fbp1). Strains overexpressing CRK1 or an allele lacking a PEST domain exhibit increased production of titan cells similarly to the fbp1∆ mutant. Conversely, CRK1 deletion results in reduced titan cell production, indicating that Crk1 stimulates titan cell formation. Crk1 phosphorylates Gpa1, which then localizes to the plasma membrane and activates the cAMP/PKA signal pathway to induce cell enlargement. Furthermore, titan cell-overproducing strains trigger increased Th1 and Th17 cytokine production in CD4+ T cells and show attenuated virulence in a mouse model of systemic cryptococcosis. Overall, our study provides insights into the regulation of titan cell formation and fungal virulence.

Suggested Citation

  • Chengjun Cao & Keyi Wang & Yina Wang & Tong-Bao Liu & Amariliz Rivera & Chaoyang Xue, 2022. "Ubiquitin proteolysis of a CDK-related kinase regulates titan cell formation and virulence in the fungal pathogen Cryptococcus neoformans," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34151-6
    DOI: 10.1038/s41467-022-34151-6
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    References listed on IDEAS

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    1. Stefano Di Talia & Jan M. Skotheim & James M. Bean & Eric D. Siggia & Frederick R. Cross, 2007. "The effects of molecular noise and size control on variability in the budding yeast cell cycle," Nature, Nature, vol. 448(7156), pages 947-951, August.
    2. Clotilde Cadart & Sylvain Monnier & Jacopo Grilli & Pablo J. Sáez & Nishit Srivastava & Rafaele Attia & Emmanuel Terriac & Buzz Baum & Marco Cosentino-Lagomarsino & Matthieu Piel, 2018. "Size control in mammalian cells involves modulation of both growth rate and cell cycle duration," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    3. Stefano Di Talia & Jan M. Skotheim & James M. Bean & Eric D. Siggia & Frederick R. Cross, 2007. "Erratum: The effects of molecular noise and size control on variability in the budding yeast cell cycle," Nature, Nature, vol. 450(7173), pages 1272-1272, December.
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