Bacterial Control of Pores Induced by the Type III Secretion System: Mind the Gap

Abstract

Type III secretion systems (T3SSs) are specialized secretion apparatus involved in the virulence of many Gram-negative pathogens, enabling the injection of bacterial type III effectors into host cells. The T3SS-dependent injection of effectors requires the insertion into host cell membranes of a pore-forming "translocon," whose effects on cell responses remain ill-defined. As opposed to pore-forming toxins that damage host cell plasma membranes and induce cell survival mechanisms, T3SS-dependent pore formation is transient, being regulated by cell membrane repair mechanisms or bacterial effectors. Here, we review host cell responses to pore formation induced by T3SSs associated with the loss of plasma membrane integrity and regulation of innate immunity. We will particularly focus on recent advances in mechanisms controlling pore formation and the activity of the T3SS linked to type III effectors or bacterial proteases. The implications of the regulation of the T3SS translocon activity during the infectious process will be discussed.

Keywords: SPATE; T3SS; cell death; membrane repair; pore formation.

Figure 1

Membrane repair and inflammasome activation mediated by T3 translocons and PFTs. Membrane injuries by PFTs or T3 translocon (T3-T) trigger an osmotic stress response, Ca²⁺ influx, and K⁺ efflux that are sensed by host cells. These responses activate innate immune responses and membrane repair mechanisms. K⁺ efflux, or possibly osmotic stress, associated with PFTs leads to the activation of the p38 MAPK and IL-1β secretion. In response to T3-pore formation, inflammasome and caspase-1 activation are also observed in association with K⁺ influx into the translocon component (T3-TC) containing vacuole. Following endocytosis, T3 translocon components can activate caspase-11 through the activation of the non-canonical inflammasome. Membrane repair mechanisms linked to Ca²⁺ influx, lysosomal exocytosis and annexin recruitment are observed. New membrane recruitment to the site of infection by the exocyst complex could also contribute to patch T3-pores.

Figure 2

Bacterial effectors regulating T3-pore formation. Upon cell contact and T3SS activation, the Yersinia YopB/D translocon components activate Rho GTPases leading to the polymerization of actin and T3-pore formation. The injected T3 effectors, such as YopK, YopE, and YopT, downregulate T3-pore formation and effector translocation. YopK directly acts on the T3 translocon. YopE and YopT inhibit RhoGTPases. EspZ shares an activity related to that of YopK by binding to the EPEC T3 translocon, inhibiting T3-pore formation and effector injection. EspC downregulates T3 pore by degrading the translocator components EspA/D, an activity shared by the EHEC EspP. EspP also downregulate the Hly PFT inserted in plasma membranes.