Abstract
Pasteurella multocida toxin (PMT), the major virulence factor responsible for zoonotic atrophic rhinitis, is a protein deamidase that activates the alpha subunit of heterotrimeric G proteins. Initial activation of G alpha-q-coupled phospholipase C-beta-1 signaling by PMT is followed by uncoupling of G alpha-q-dependent signaling, causing downregulation of downstream calcium and mitogenic signaling pathways. Here, we show that PMT decreases endogenous and exogenously expressed G alpha-q protein content in host cell plasma membranes and in detergent resistant membrane (DRM) fractions. This membrane depletion of G alpha-q protein was dependent upon the catalytic activity of PMT. Results indicate that PMT-modified G alpha-q redistributes within the host cell membrane from the DRM fraction into the soluble membrane and cytosolic fractions. In contrast, PMT had no affect on G alpha-s or G beta protein levels, which are not substrate targets of PMT. PMT also had no affect on G alpha-11 levels, even though G alpha-11 can serve as a substrate for deamidation by PMT, suggesting that membrane depletion of PMT-modified G-alpha-q has specificity.
Highlights
Pasteurella multocida toxin (PMT) is the major virulence factor responsible for atrophic rhinitis, pasteurellosis, and dermonecrosis caused by infection with toxigenic capsular type D and someA strains of Pasteurella multocida
We previously showed that microinjection of PMT into voltage-clamped Xenopus oocytes invoked a rapid Ca2+ -dependent Clcurrent, which involved activation of Gαq/11 -phospholipase C β-1 (PLCβ1) [9]
A similar initial activation and subsequent downregulation of PMT-stimulated Ca2+ and mitogenic signaling was evidenced in mammalian cells through studies involving cell cycle analysis [21,46]
Summary
Pasteurella multocida toxin (PMT) is the major virulence factor responsible for atrophic rhinitis, pasteurellosis, and dermonecrosis caused by infection with toxigenic capsular type D and someA strains of Pasteurella multocida (reviewed in [1]). Pasteurella multocida toxin (PMT) is the major virulence factor responsible for atrophic rhinitis, pasteurellosis, and dermonecrosis caused by infection with toxigenic capsular type D and some. PMT is subsequently endocytosed and released from the late endosomes into the cytosol in a pH dependent manner [3,4,5], where it targets heterotrimeric G-proteins and modulates their downstream signaling pathways (reviewed in [6]). PMT stimulates phospholipase C β-1 (PLCβ1) signaling through its preferential activation of Gαq of the Gαq/11 family of G-proteins [9,10]. PMT increases the intracellular cytoplasmic concentration of Ca2+ and activates mitogenic signaling pathways, leading to increased cellular proliferation and in some cell types cell differentiation [9,12].
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