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<p><i>Edwardsiella piscicida</i> T3SS protein EseJ plays a dual role. As a regulator, EseJ suppresses type 1 fimbriae, inhibiting macrophage apoptosis stimulated by FimH. As an effector, it promotes <i>E. piscicida</i> replication in host cells. In this study, the mechanism of EseJ in converting apoptotic cell rounding to pyroptotic cell rupture in murine macrophages was explored. Overexpressing EseJ in the Δ<i>fimH</i> strain suppresses pyroptosis in murine macrophages by deactivating the caspase-8 and NLRP3 inflammasome. This is evidenced by pretreatment with the pharmacological inhibitors z-IETD-fmk (a caspase-8 inhibitor) and MCC950 (an NLRP3 inhibitor), or by knocking down caspase-8 and NLRP3. This finding lends support to the idea that EseJ is involved in the inhibition of pyroptosis. Furthermore, EseJ translocation significantly increased the phosphorylation of TAK1, while reducing necroptosis, which is driven by the activation of receptor-interacting protein kinase 1 (RIPK1) and the phosphorylation of mixed lineage kinase domain-like (p-MLKL). Therefore, EseJ inhibits PANoptosis (pyroptosis, apoptosis and necroptosis) by activating TAK1 and disrupting the formation of the NLRP3-caspase-8-RIPK1 PANoptosome. Interestingly, <i>E. piscicida</i> is attenuated upon EseJ depletion, especially in the early phase after infection. These findings reveal a new way in which <i>E. piscicida</i> circumvents host cell death pathways, thereby increasing its virulence.</p>

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T3SS effector EseJ in Edwardsiella piscicida inhibits PANoptosis in macrophages

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Tian Tian He,
  • Pu Yu Tang,
  • Xiu Long Jiang,
  • Shan Shan Sun,
  • Pin Nie,
  • Hai Xia Xie

摘要

Edwardsiella piscicida T3SS protein EseJ plays a dual role. As a regulator, EseJ suppresses type 1 fimbriae, inhibiting macrophage apoptosis stimulated by FimH. As an effector, it promotes E. piscicida replication in host cells. In this study, the mechanism of EseJ in converting apoptotic cell rounding to pyroptotic cell rupture in murine macrophages was explored. Overexpressing EseJ in the ΔfimH strain suppresses pyroptosis in murine macrophages by deactivating the caspase-8 and NLRP3 inflammasome. This is evidenced by pretreatment with the pharmacological inhibitors z-IETD-fmk (a caspase-8 inhibitor) and MCC950 (an NLRP3 inhibitor), or by knocking down caspase-8 and NLRP3. This finding lends support to the idea that EseJ is involved in the inhibition of pyroptosis. Furthermore, EseJ translocation significantly increased the phosphorylation of TAK1, while reducing necroptosis, which is driven by the activation of receptor-interacting protein kinase 1 (RIPK1) and the phosphorylation of mixed lineage kinase domain-like (p-MLKL). Therefore, EseJ inhibits PANoptosis (pyroptosis, apoptosis and necroptosis) by activating TAK1 and disrupting the formation of the NLRP3-caspase-8-RIPK1 PANoptosome. Interestingly, E. piscicida is attenuated upon EseJ depletion, especially in the early phase after infection. These findings reveal a new way in which E. piscicida circumvents host cell death pathways, thereby increasing its virulence.