Pasteurella multocida toxin interaction with host cells: entry and cellular effects

Abstract

The mitogenic dermonecrotic toxin from Pasteurella multocida (PMT) is a 1285-residue multipartite protein that belongs to the A-B family of bacterial protein toxins. Through its G-protein-deamidating activity on the α subunits of heterotrimeric G(q)-, G(i)- and G(12/13)-proteins, PMT potently stimulates downstream mitogenic, calcium, and cytoskeletal signaling pathways. These activities lead to pleiotropic effects in different cell types, which ultimately result in cellular proliferation, while inhibiting cellular differentiation, and account for the myriad of physiological outcomes observed during infection with toxinogenic strains of P. multocida.

Fig. 1

A schematic diagram of the overall structure of PMT. PMT-N (residues 1–568) and the known C-terminal structural domains (C1–C3) of PMT-C (residues 569–1285) are indicated along with their known or putative functions

Fig. 2

Proposed model of PMT entry and trafficking. Tfn transferrin, TfnR transferrin receptor, CT cholera toxin, Rab5 GTPase marker of recycling endosomes, TGN trans-Golgi network, ER endoplasmic reticulum, SM/PC sphingomyelin/PC receptors of PMT, Arf6-CA constitutively active Arf6 GTPase, Arf6-DN dominantly negative Arf6, CcD cytochalasin D, LY294002 PI3 K inhibitor of early endosome-recycling endosome fusion, Noc nocodazole, BafA1 bafilomycin A1, Bfa brefeldin A. [Adapted from (Repella et al. 2011)]

Fig. 3

Signaling pathways modulated by PMT and their cellular outcomes