| الوصف: |
SummaryThe transcription factor TFEB promotes lysosomal and autophagic capacity in response to stresses like amino acid depletion. Additionally, TFEB drives expression of immune-responsive and immuno-protective genes in response to LPS, phagocytosis, and bacteria such asEscherichia coli(E. coli) andStaphylococcus aureus. Consistent with a role for TFEB in promoting immunity and bactericidal activity, intracellular pathogens likeMycobacteriumandSalmonellaappear to repress TFEB, whereas compounds that promote TFEB production or activity enhance macrophage killing ofSalmonella. Intriguingly,Salmonella entericasv. Typhimurium (S.Typhimurium) was observed to actively stimulate TFEB, implying a benefit toSalmonelladuring infection. To better understand the relationship betweenS.Typhimurium infection and TFEB, we assessed ifS.Typhimurium regulated TFEB in murine macrophages in a manner dependent on infection conditions. Here, we show that macrophages that engulfed late-logarithmic grownSalmonellaaccumulated and maintained nuclear TFEB, comparable to macrophages that engulfedE. coli. In contrast, stationary-phaseS.Typhimurium infection of macrophages actively delayed TFEB nuclear mobilization over the first hour of infection. The delay in TFEB nuclear mobilization was not observed in macrophages that engulfed heat-killed stationary-phaseSalmonella, orSalmonellalacking functional SPI-1 and SPI-2 type three secretion systems.S.Typhimurium mutated in the master virulence regulatorphoPor the secreted effector genessifA, andsopDalso showed normal TFEB nuclear translocation. Interestingly, whileE. colisurvived better inTfeb-/-macrophages,S.Typhimurium growth was similar in wild-type andTfeb-/-macrophages. Yet, priming macrophages with phagocytosis enhanced the killing ofSalmonellain wild-type, but not inTfeb-/-macrophages. Collectively,S.Typhimurium seems to orchestrate TFEB in a manner dependent on infection conditions, while conditions that disturb this context-dependent control of TFEB, such as forcing activation of TFEB seems to be detrimental toSalmonellasurvival. |
