Pde1 phosphodiesterase modulates cyclic AMP levels through a protein kinase A-mediated negative feedback loop in Cryptococcus neoformans

Julie K. Hicks, Yong Sun Bahn, Joseph Heitman

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

The virulence of the human pathogenic fungus Cryptococcus neoformans is regulated by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling cascade that promotes mating and the production of melanin and capsule. In this study, genes encoding homologs of the Saccharomyces cerevisiae low- and high-affinity phosphodiesterases, PDE1 and PDE2, respectively, were deleted in serotype A strains of C. neoformans. The resulting mutants exhibited moderately elevated levels of melanin and capsule production relative to the wild type. Epistasis experiments indicate that Pde1 functions downstream of the Gα subunit Gpa1, which initiates cAMP-dependent signaling in response to an extracellular signal. Previous work has shown that the PKA catalytic subunit Pka1 governs cAMP levels via a negative feedback loop. Here we show that a pde1Δ. pka1Δ mutant strain exhibits cAMP levels that are dramatically increased (∼15-fold) relative to those in a pka1Δ single mutant strain and that a site-directed mutation in a consensus PKA phosphorylation site reduces Pde1 function. These data provide evidence that fluctuations in cAMP levels are modulated by both Pka1-dependent regulation of Pde1 and another target that comprise a robust negative feedback loop to tightly constrain intracellular cAMP levels.

Original languageEnglish
Pages (from-to)1971-1981
Number of pages11
JournalEukaryotic Cell
Volume4
Issue number12
DOIs
Publication statusPublished - 2005 Dec

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

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