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Pasteurella multocida toxin activates Gbetagamma dimers of heterotrimeric G proteins

Inga Preuss1, Barbara Kurig, Bernd Nürnberg

  • 1Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Germany.

Cellular Signalling
|January 13, 2009
PubMed

Insights

Pasteurella multocida toxin (PMT) activates Gbetagamma signaling, stimulating phosphoinositide 3-kinase gamma. This Gbetagamma pathway is essential for PMT-induced Galpha signaling, revealing a novel mechanism of virulence.

Area of Science:

  • Microbiology
  • Cellular Biology
  • Toxicology

Background:

  • Pasteurella multocida toxin (PMT) is a key virulence factor causing Pasteurellosis.
  • PMT activates small GTPase RhoA, MAP kinase ERK, and STAT proteins through G(q) and G(12/13) G proteins.
  • PMT stimulates PLCbeta via Galpha(q), increasing inositol phosphates, and inhibits adenylyl cyclase via Galpha(i).

Purpose of the Study:

  • To investigate the role of Gbetagamma signaling in PMT-mediated cellular responses.
  • To determine if Gbetagamma is involved in PMT activation of Galpha proteins.
  • To elucidate the complete signaling pathway of the mitogenic Pasteurella multocida toxin.

Main Methods:

  • Utilized a PIP(3)-binding pleckstrin homology (PH) domain-containing protein to detect phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) formation at the plasma membrane.
  • Employed Galpha(q) mutants unable to bind or release Gbetagamma.
  • Used Gbetagamma sequestration techniques to assess its necessity in PMT signaling.

Main Results:

  • PMT activates Gbetagamma signaling, leading to the stimulation of phosphoinositide 3-kinase (PI3K) gamma.
  • Activation of Gbetagamma by PMT results in the formation of PIP(3).
  • Gbetagamma signaling is indispensable for PMT-induced Galpha signaling, as demonstrated by non-activated Galpha(q) mutants and inhibited signaling upon Gbetagamma sequestration.

Conclusions:

  • PMT utilizes both Galpha and Gbetagamma subunits for its signaling.
  • Gbetagamma activation is a critical upstream event for PMT-induced Galpha-mediated cellular effects.
  • This study reveals a novel Gbetagamma-dependent mechanism in PMT virulence, expanding the understanding of its pathogenic actions.

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