Scheme of modulation of signaling pathways in phagocytes by protein effectors/toxins of Yersinia pseudotuberculosis (IMAGE)
Caption
To maintain a balance between the death of the host cell and saving a niche for survival and spread, Yptb uses a set of toxic proteins. The proteins exert their action through different signaling pathways. The activity of the crucial signaling pathways that determine the type of cell death is controlled simultaneously by several proteins, which can both mutually enhance each other’s effects or compete with each other. YopM activates PRK2 by preliminary binding and activating RSK1; caspase-3 is a cofactor in the activation of the latter. The downstream effector STAT3 stimulates the expression of the anti-inflammatory cytokine IL-10. Additionally, YopM has an anti-inflammatory effect through inhibition of the activity of caspase-1, which is part of the pyrin-inflammasome complex, and the synthesis of the pro-inflammatory cytokine IL-1, which induces a pro-inflammatory type of cell death, pyroptosis. YopM also exerts an anti-inflammatory effect through inhibition of the pro-inflammatory activity (activation of inflammasome assembly) of YopE and YopT. YopJ induces apoptotic cell death in macrophages but not in neutrophils through activation of caspase-8. In addition, YopJ prevents activation of the MAPKs (including TAK1 and MAP2 kinase) and downstream activation of JNK and/or p38 and NF-κB-dependent pathways. Redundantly, YopJ inhibits biosynthesis of PGE2, which is involved in the activation of NF-κB-dependent transcription of IL-1β. Thus, inhibiting the MAPK cascade leads to blocking IL-1β secretion and preventing pyroptosis. However, YopJ can also have a pro-inflammatory effect, activating inflammasome assembly via the RIPK1/caspase-8-dependent pathway, as well as stimulating GSDME- and GSDMD-dependent and controlling by RIPK1 and caspase-8 ROS activation and pore formation in neutrophils and macrophages, respectively. YpkA inhibits Rho GTPases and the rearrangement of the actin cytoskeleton directly or through phosphorylation of Gαq. In addition, YpkA can promote pore formation through phosphorylation of actin-binding proteins, such as VASP, EVL, WASP, WIP, and gelsolin. These pathways lead to pyroptosis. Meanwhile, the anti-inflammatory effect of YpkA also occurs through stimulation of caspase-3-mediated apoptosis. YopH inhibits ROS generation in neutrophils and apparently limits inflammation through inhibiting SKAP2-dependent ERK1/2 signaling pathway and FcγR-dependent signaling pathway, including phosphorylation of the proximal signaling proteins such as Syk, SLP-76, PLCγ2, and PRAM-1. YopE suppresses Rho GTPases and selectively inhibits caspase-1 and the release of IL-1β to protect host cells from pyroptosis via inactivating Rac2. Inhibition of RhoA, on the contrary, results in inflammasome activation. YopE manipulates the assembly of inflammasomes only in the absence of YopM. YopT cleaves RhoA GTPase, leading to the disruption of actin structures and contributing to pore formation and the anti-phagocytic effect of Yersinia. YopT also activates inflammasome assembly and cell death by pyroptosis. In this case, YopT acts slower than YopE and activates inflammasome assembly only in the absence of YopM. CNFY constitutively activates Rho GTPases. This leads to STAT3 activation, which may be involved in the anti-inflammatory response, including iNOS inhibition as described for HLT (identified as CNFY) in the early stage of incubation. In addition, RhoA stimulation by CNFY leads to suppression of inflammasome assembly. Conversely, Rac1 activation by the toxin through the PI3K/Akt/NF-κB signaling pathway prevents apoptosis. YPM binds directly to MHC II molecules and activates both innate immune cells and T cells, followed by a massive release of pro-inflammatory cytokines. Simultaneously, YPM stimulates IL-4 release, strengthening the Th2 immune profile apparently aimed to restrict inflammatory death of phagocytes. TsTYp modulates the accumulation of cAMP and ROS-mediated apoptosis, negatively associated with cAMP level. The toxin affects the level of cAMP in neutrophils and mononuclear cells in the opposite way. TcpYI blocks TIR signaling via binding to TIR. Akt, protein kinase B; cAMP, cyclic adenosine monophosphate; CNFY, cytotoxic necrotizing factor of Yersinia pseudotuberculosis; EVL, Ena/VASP-like protein; FADD, Fas-associated protein with death domain; Gαq, Gq protein alpha subunit; GSDM, gasdermin; JNK, c-Jun N-terminal kinase; ERK1/2, extracellular signal-regulated kinase 1/2; FcγR, Fc gamma receptor; GTPase, guanosine triphosphate hydrolase; HLT, heat-labile toxin; IL, interleukin; iNOS, inducible nitric oxide synthase; M, macrophage; MAPKs, mitogen-activated protein kinases; MHC, major histocompatibility complex; N, neutrophil; NF-κB, nuclear factor kappa B; p38, p38 mitogen-activated protein kinase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PLCγ2, phospholipase Cγ 2; PM, plasma membrane of the phagocyte; PRAM-1, PML-RARA regulated adaptor molecule 1; PRK2, protein kinase C-related kinase 2; RIPK1, receptor-interacting serine/threonine protein kinase 1; ROS, reactive oxygen species; RSK1, 90-kDa ribosomal S6 kinase; SLP-76, SH2 domain-containing leukocyte protein of 76 kDa; SKAP2, Src kinase-associated phosphoprotein-2; STAT3, signal transducer and activator of transcription 3; Syk, spleen tyrosine kinase; TAK1, transforming growth factor beta-activated kinase 1; TcpYI, Toll/interleukin-1 receptor domain-containing virulence protein of Y. pseudotuberculosis; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptor; TsTYp, thermostable toxin of Y. pseudotuberculosis; VASP, vasodilator-stimulated phosphoprotein; WASP, Wiskott-Aldrich syndrome protein; WIP, WASP-interacting protein; YPM, Y. pseudotuberculosis-derived mitogen.
Credit
Lyudmila S. Dolmatova
Usage Restrictions
Credit must be given to the creator. Only noncommercial uses of the work are permitted.
License
CC BY-NC