| First Author | Zheng Y | Year | 2011 |
| Journal | PLoS Pathog | Volume | 7 |
| Issue | 4 | Pages | e1002026 |
| PubMed ID | 21533069 | Mgi Jnum | J:294782 |
| Mgi Id | MGI:6458623 | Doi | 10.1371/journal.ppat.1002026 |
| Citation | Zheng Y, et al. (2011) A Yersinia effector with enhanced inhibitory activity on the NF-kappaB pathway activates the NLRP3/ASC/caspase-1 inflammasome in macrophages. PLoS Pathog 7(4):e1002026 |
| abstractText | A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKbeta to cause TLR4-dependent apoptosis in naive macrophages. A YopJ isoform in Y. pestis KIM (YopJ(KIM)) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJ(KIM) causes increased apoptosis, caspase-1 activation, and secretion of IL-1beta in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJ(KIM) in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJ(KIM) were important for enhanced apoptosis, caspase-1 activation, and IL-1beta secretion. As compared to YopJ(CO92), YopJ(KIM) displayed an enhanced capacity to inhibit phosphorylation of IkappaB-alpha in macrophages and to bind IKKbeta in vitro. YopJ(KIM) also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1beta secretion occurred in IKKbeta-deficient macrophages infected with Y. pestis expressing YopJ(CO92), confirming that the NF-kappaB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1beta in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naive macrophages in response to infection with a pathogen that inhibits IKKbeta and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways. |
