RESUMO
Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.
Assuntos
Fenótipo Secretor Associado à Senescência , Febre Tifoide , Humanos , Febre Tifoide/metabolismo , Mutagênicos/metabolismo , Senescência Celular/fisiologia , Mitocôndrias/metabolismo , DNA Mitocondrial/metabolismo , Salmonella , FenótipoRESUMO
The synthesis of the cell-wall peptidoglycan during bacterial cell division is mediated by a multiprotein machine, called the divisome. The essential membrane protein complex of FtsB, FtsL and FtsQ (FtsBLQ) is at the heart of the divisome assembly cascade in Escherichia coli. This complex regulates the transglycosylation and transpeptidation activities of the FtsW-FtsI complex and PBP1b via coordination with FtsN, the trigger for the onset of constriction. Yet the underlying mechanism of FtsBLQ-mediated regulation is largely unknown. Here, we report the full-length structure of the heterotrimeric FtsBLQ complex, which reveals a V-shaped architecture in a tilted orientation. Such a conformation could be strengthened by the transmembrane and the coiled-coil domains of the FtsBL heterodimer, as well as an extended ß-sheet of the C-terminal interaction site involving all three proteins. This trimeric structure may also facilitate interactions with other divisome proteins in an allosteric manner. These results lead us to propose a structure-based model that delineates the mechanism of the regulation of peptidoglycan synthases by the FtsBLQ complex.
Assuntos
Proteínas de Escherichia coli , Proteínas de Escherichia coli/metabolismo , Proteínas de Ciclo Celular/metabolismo , Peptidoglicano/metabolismo , Proteínas de Membrana/metabolismo , Divisão Celular , Escherichia coli/metabolismo , Proteínas de Bactérias/metabolismoRESUMO
The dynamic assembly of the cell wall is key to the maintenance of cell shape during bacterial growth. Here, we present a method for the analysis of Escherichia coli cell wall growth at high spatial and temporal resolution, which is achieved by tracing the movement of fluorescently labeled cell wall-anchored flagellar motors. Using this method, we clearly identify the active and inert zones of cell wall growth during bacterial elongation. Within the active zone, the insertion of newly synthesized peptidoglycan occurs homogeneously in the axial direction without twisting of the cell body. Based on the measured parameters, we formulate a Bernoulli shift map model to predict the partitioning of cell wall-anchored proteins following cell division.
Assuntos
Parede Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Complexos Multiproteicos/metabolismo , Divisão Celular , Escherichia coli/crescimento & desenvolvimento , Flagelos/metabolismo , Fluorescência , Peptidoglicano/metabolismoRESUMO
The genomic sequence was determined for Xanthomonas axonopodis pv. glycines strain 12609, isolated in Taiwan. Based on the genome sequence, we predicted the encoded genes, rRNA, tRNA, a plasmid sequence, secretion systems, cyclic GMP- and cyclic di-GMP-mediated pathways, and the gene cluster rpfABCHGDE (regulation of pathogenicity factor).