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<p>Toxin-antitoxin (TA) systems are pivotal in the bacterial stress response, yet signals controlling their activation and functional integration into virulence remain poorly understood. This study unveils a multi-layered signaling network centered on antitoxin HigA in the fish pathogen <i>Edwardsiella piscicida</i>. We identify XreR, a novel XRE-family transcriptional regulator, as a direct transcriptional activator of <i>higA</i>, and demonstrate that XreR-dependent upregulation of HigA modulates virulence. Beyond its antitoxin function, HigA acts as a transcription factor that directly activates <i>ethB</i>, a hemolysin activator gene, thereby enhancing hemolysis. However, excessive hemolysis triggers a host pyroptosis-like response, compromising intramacrophage survival and revealing a dual role for EthB in virulence. Based on the hypersensitivity of <i>xreR</i>OE to oxidative stress, we reveal that HigA attenuates oxidative stress tolerance by directly repressing the RpoS-KatG pathway. This repression is counterbalanced by Lon protease, which degrades HigA under oxidative stress, representing a critical post-translational negative regulatory mechanism. Collectively, our findings establish the XreR-HigA-Lon axis as a central regulatory module. This not only governs hemolytic virulence via the XreR-HigA-EthB pathway but also mediates oxidative tolerance through the Lon-HigA-RpoS-KatG pathway, thereby revealing the dual role of HigA in coordinating pathogenicity and stress adaptation. This study offers a new paradigm for understanding how bacterial pathogens balance infection progression with host environmental constraints.</p>

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A molecular switch: antitoxin HigA integrates transcriptional activation by XreR and proteolytic clearance by Lon to balance virulence and stress adaptation in the fish pathogen Edwardsiella piscicida

  • 期刊论文

  • 发表日期：

    2026年5月4日

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  • Yin Gou,
  • Jingjing Sui,
  • Jinggang Dong,
  • Jun Li,
  • Baocun Zhang,
  • Qingjian Fang,
  • Guoqing Wang,
  • Hanjie Gu,
  • Yonghua Hu

摘要

Toxin-antitoxin (TA) systems are pivotal in the bacterial stress response, yet signals controlling their activation and functional integration into virulence remain poorly understood. This study unveils a multi-layered signaling network centered on antitoxin HigA in the fish pathogen Edwardsiella piscicida. We identify XreR, a novel XRE-family transcriptional regulator, as a direct transcriptional activator of higA, and demonstrate that XreR-dependent upregulation of HigA modulates virulence. Beyond its antitoxin function, HigA acts as a transcription factor that directly activates ethB, a hemolysin activator gene, thereby enhancing hemolysis. However, excessive hemolysis triggers a host pyroptosis-like response, compromising intramacrophage survival and revealing a dual role for EthB in virulence. Based on the hypersensitivity of xreROE to oxidative stress, we reveal that HigA attenuates oxidative stress tolerance by directly repressing the RpoS-KatG pathway. This repression is counterbalanced by Lon protease, which degrades HigA under oxidative stress, representing a critical post-translational negative regulatory mechanism. Collectively, our findings establish the XreR-HigA-Lon axis as a central regulatory module. This not only governs hemolytic virulence via the XreR-HigA-EthB pathway but also mediates oxidative tolerance through the Lon-HigA-RpoS-KatG pathway, thereby revealing the dual role of HigA in coordinating pathogenicity and stress adaptation. This study offers a new paradigm for understanding how bacterial pathogens balance infection progression with host environmental constraints.