Yersinia type III secretion: send in the effectors

Abstract

Pathogenic Yersinia spp (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) have evolved an exquisite method for delivering powerful effectors into cells of the host immune system where they inhibit signaling cascades and block the cells' response to infection. Understanding the molecular mechanisms of this system has provided insight into the processes of phagocytosis and inflammation.

Figure 1.

Secretion of Yops by the Ysc injectisome and translocation across the target cell membrane. When Yersinia are placed at 37°C in a rich environment, the Ysc injectisome is installed and a stock of Yop proteins is synthesized. During their intrabacterial stage, some Yops are capped with their specific Syc chaperone. Upon contact with a eukaryotic target cell, the adhesins YadA or Inv interact with integrins and the bacterium docks at the cell's surface. Then, the secretion channel opens and Yops are exported. YopB and YopD form a pore in the target cell plasma membrane, and the effector Yops are translocated across this membrane into the eukaryotic cell cytosol. YopM migrates to the nucleus. EM, outer membrane; P, peptidoglycen; IM, plasma membrane.

Figure 2.

Antiphagocytic action of the Yops. Upon contact with a phagocyte receptor (R), a signaling cascade is triggered and GTP-bound Rho family members (RhoA, Rac-1, Cdc42) promote actin polymerization. YopE, acting as a GAP, down-regulates Rac-1, Cdc42, and RhoA. The YopT protease cleaves the COOH terminus of RhoA, Rac, and Cdc42, liberating them from the plasma membrane. The YpkA/YopO kinase becomes autophosphorylated upon contact with actin and interacts with RhoA and Rac-1. The PTPase YopH is targeted to focal adhesions and to other protein complexes where it dephosphorylates proteins such as the focal adhesion kinase (Fak), p130Cas, and SKAP-HOM.

Figure 3.

Down-regulation of the inflammatory response. YopP binds and blocks the IkB kinase β (IKKβ), which inhibits the phosphorylation and degradation of IkB, the inhibitor of NF-kB. This in turn prevents the migration of the transcription factor NF-κB to the nucleus. The absence of NF-κB in the nucleus prevents transcription of antiapoptotic genes and several proinflammatory genes including the TNF-α gene. YopP also blocks the MKKs, inhibiting the activation of MAPK, which abrogates activation of CREB, another transcription factor involved in the immune response. YopP induces apoptosis in macrophages, either directly by acting upstream of Bid or indirectly by blocking the synthesis of NF-κB–dependent antiapoptotic factors. Yop H inhibits the production of monocyte chemoattractant protein 1 (MCP-1) by dephosphorylating key players in the phosphatidylinositol 3-kinase/Akt pathway.