Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Kevin M. Brown, L. David Sibley

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Apicomplexan parasites rely on cyclic nucleotide-dependent kinases for host cell infection, yet the mechanisms that control their activation remain unknown. Here we show that an apically localized guanylate cyclase (GC) controls microneme secretion and lytic growth in the model apicomplexan Toxoplasma gondii. Cell-permeable cGMP reversed the block in microneme secretion seen in a knockdown of TgGC, linking its function to production of cGMP. TgGC possesses an N-terminal P-type ATPase domain fused to a C-terminal heterodimeric guanylate cyclase domain, an architecture found only in Apicomplexa and related protists. Complementation with a panel of mutants revealed a critical requirement for the P-type ATPase domain for maximum GC function. We further demonstrate that knockdown of TgGC in vivo protects mice from lethal infection by blocking parasite expansion and dissemination. Collectively, this work demonstrates that cGMP-mediated signaling in Toxoplasma relies on a multi-domain architecture, which may serve a conserved role in related parasites.

Original languageEnglish
Pages (from-to)804-816.e6
JournalCell Host and Microbe
Volume24
Issue number6
DOIs
StatePublished - Dec 12 2018

Keywords

  • apicomplexan parasite
  • auxin-inducible degron
  • calcium
  • cyclic nucleotides
  • egress
  • host-pathogen interaction
  • invasion
  • regulated protein stability
  • secretion
  • signaling

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