Type III secretion translocation pores of Yersinia enterocolitica trigger maturation and release of pro-inflammatory IL-1β

Abstract

Bacteria from the genus Yersinia deliver a number of effectors into host cells via type III secretion (T3S). Injected Yop effectors interfere and prevent pro-inflammatory warning signals by hijacking the host's intracellular machinery. While macrophages infected by wild-type Yersinia enterocolitica did not release mature IL-1beta, macrophages infected by Y. enterocolitica deprived of all effectors released mature IL-1beta. Surprisingly, macrophages infected by Y. enterocolitica deficient for secretion of all T3S proteins, including effectors and translocators, did not release mature IL-1beta. Using different genetic constructs, we show that insertion of T3S translocation pores trigger activation of caspase-1, maturation of proIL-1beta and release of mature IL-1beta, which occurs independently of cell osmotic lysis. These data show that T3S translocation is intrinsically a pro-inflammatory phenomenon. However, in the case of Yersinia, this effect is neutralized by the action of effectors.

Caspase-1 Activation in Macrophages Infected with Yersinia pestis KIM Requires the Type III Secretion System Effector YopJ

“…It has been previously shown that Yop effectors inhibit expression and secretion of IL-1␤ in the macrophage-like cell line Mf4/4 infected with Y. enterocolitica (47,49). BMDMs were infected with different Y. pseudotuberculosis and Y. pestis strains to determine whether the T3SS and Yops of these species play a similar role in the inhibition of IL-1␤ release.…”

“…Previous studies have examined caspase-1 activation and IL-1␤ secretion in macrophages infected with Yersinia species (2,47,49). Schotte et al (47) examined these responses after they infected murine Mf4/4 macrophage-like cells with Y. enterocolitica E40 as well as different single or multiple yop mutants of this strain.…”

“…Overall, these findings implicated YopP as an inhibitor of pro-IL-1␤ synthesis and YopE and YopT as inhibitors of caspase-1 activation. Shin and Cornelis (49) obtained evidence that pores generated by the T3SS translocation channel trigger activation of caspase-1 in Mf4/4 cells infected with a Y. enterocolitica E40 multi-yop effector mutant. Thus, in their model (49), YopE and YopT inhibit activation of caspase-1 by counteracting T3SS-dependent pore formation (51).…”

“…Shin and Cornelis (49) obtained evidence that pores generated by the T3SS translocation channel trigger activation of caspase-1 in Mf4/4 cells infected with a Y. enterocolitica E40 multi-yop effector mutant. Thus, in their model (49), YopE and YopT inhibit activation of caspase-1 by counteracting T3SS-dependent pore formation (51). More recently, Bergsbaken and Cookson obtained evidence that Y. pseudotuberculosis strain YPIII could induce caspase-1 activation in murine bonemarrow derived macrophages (BMDMs) that were activated by preexposure to LPS (2).…”

Protein Export According to Schedule: Architecture, Assembly, and Regulation of Type III Secretion Systems from Plant- and Animal-Pathogenic Bacteria

“…Previous mutant studies of Yersinia spp. revealed that it is the presence of the T3S translocon that triggers proinflammatory responses, which are in turn suppressed by translocated effector proteins (503). This predicted feedback regulation might itself be controlled by the degradation of effector proteins inside the host cell, as shown for YopE from Yersinia spp., which is degraded by the eukaryotic ubiquitination machinery.…”