The Edwardsiella T3SS effector EseJ enhances NF-κB signaling by stabilizing p65 and promoting TAK1 phosphorylation
4 affiliations
- 1Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- 2State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- 3Universityof Chinese Academy of Sciences, Beijing, China
- 4Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Centre, Kansas, Missouri, United States of America
Abstract
Edwardsiella piscicida PPD130/91 is an important pathogen that infects both fish and humans. Upon infection, E. piscicida induces strong inflammatory responses through its type III secretion system (T3SS). The underlying mechanisms remain to be defined. Here, we demonstrate that E. piscicida T3SS effector EseJ activates the NF-κB pathway in macrophages, leading to increased transcription and secretion of multiple pro-inflammatory cytokines (e.g., IL-1β and IL-6). EseJ orchestrates NF-κB signaling by interfering with two ubiquitin-dependent mechanisms that are mediated by separate functional domains of EseJ. EseJ binds to the NF-κB subunit p65 via its N-terminal region of amino acids 1–242, preventing the K48-linked polyubiquitination of p65 and its subsequent degradation by the proteasome. This maintains elevated levels of total and phosphorylated p65 (p-p65), facilitating p65 nuclear translocation and enhancing its transcriptional activity. EseJ also interacts with TAK1 and TRAF6 (both are upstream of the NF-κB signaling pathway) via its central domain (aa 243–532), thereby promoting the formation of a stable TRAF6-TAK1 complex. This interaction increases the TRAF6-dependent K27-linked polyubiquitination of TAK1, driving TAK1 phosphorylation and the subsequent activation of the IKK-IκB-NF-κB cascade. Inhibiting TAK1 abrogates this signaling, confirming the essential role of TAK1 in EseJ-induced NF-κB activation. In vivo studies using zebrafish larvae also demonstrated that EseJ is required for E. piscicida to induce the production of pro-inflammatory cytokines. Together, we provide evidence that EseJ targets both TAK1 and p65 to promote NF-κB-dependent inflammatory responses. Given the similarities among EseJ homologues in other bacteria, our finding may reveal a conserved effector-mediated immune signaling across diverse Gram-negative pathogens. Author summary: Bacterial pathogens often use specialized molecular syringes, known as type III secretion systems, to inject effector proteins directly into host cells and manipulate immune defenses. Edwardsiella piscicida is a significant pathogen affecting aquaculture and human health, known for triggering inflammation, though the precise bacterial factors driving this response have remained unclear. In this study, we identify the secreted bacterial effector EseJ as a central driver of host inflammatory signaling. We demonstrate that EseJ functions through a dual-action mechanism, using two distinct structural regions to hijack host ubiquitin pathways and overactivate the immune regulator NF-κB. Specifically, EseJ stabilizes the key signaling protein TAK1 while simultaneously protecting the transcription factor p65 from degradation, leading to sustained production of pro-inflammatory cytokines. Disruption of EseJ reduces inflammation during infection in zebrafish models, confirming its critical role in vivo. Because EseJ is highly conserved across Edwardsiella species, our findings reveal an underappreciated strategy used by these pathogens to exacerbate host inflammation, offering new insights into bacterial virulence and potential therapeutic targets for combating infection.
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BibTeX
@article{he2026edwardsiella,
title = {{The Edwardsiella T3SS effector EseJ enhances NF-κB signaling by stabilizing p65 and promoting TAK1 phosphorylation}},
author = {Tian Tian He and Pu Yu Tang and Qian Ru Zhao and Jie Zhang and Pin Nie and Hong Bing Yu and Hai Xia Xie},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014260},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014260},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Edwardsiella T3SS effector EseJ enhances NF-κB signaling by stabilizing p65 and promoting TAK1 phosphorylation
AU - Tian Tian He
AU - Pu Yu Tang
AU - Qian Ru Zhao
AU - Jie Zhang
AU - Pin Nie
AU - Hong Bing Yu
AU - Hai Xia Xie
PY - 2026
DA - 2026/09/15
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014260
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014260
AB - Edwardsiella piscicida PPD130/91 is an important pathogen that infects both fish and humans. Upon infection, E. piscicida induces strong inflammatory responses through its type III secretion system (T3SS). The underlying mechanisms remain to be defined. Here, we demonstrate that E. piscicida T3SS effector EseJ activates the NF-κB pathway in macrophages, leading to increased transcription and secretion of multiple pro-inflammatory cytokines (e.g., IL-1β and IL-6). EseJ orchestrates NF-κB signaling by interfering with two ubiquitin-dependent mechanisms that are mediated by separate functional domains of EseJ. EseJ binds to the NF-κB subunit p65 via its N-terminal region of amino acids 1–242, preventing the K48-linked polyubiquitination of p65 and its subsequent degradation by the proteasome. This maintains elevated levels of total and phosphorylated p65 (p-p65), facilitating p65 nuclear translocation and enhancing its transcriptional activity. EseJ also interacts with TAK1 and TRAF6 (both are upstream of the NF-κB signaling pathway) via its central domain (aa 243–532), thereby promoting the formation of a stable TRAF6-TAK1 complex. This interaction increases the TRAF6-dependent K27-linked polyubiquitination of TAK1, driving TAK1 phosphorylation and the subsequent activation of the IKK-IκB-NF-κB cascade. Inhibiting TAK1 abrogates this signaling, confirming the essential role of TAK1 in EseJ-induced NF-κB activation. In vivo studies using zebrafish larvae also demonstrated that EseJ is required for E. piscicida to induce the production of pro-inflammatory cytokines. Together, we provide evidence that EseJ targets both TAK1 and p65 to promote NF-κB-dependent inflammatory responses. Given the similarities among EseJ homologues in other bacteria, our finding may reveal a conserved effector-mediated immune signaling across diverse Gram-negative pathogens. Author summary: Bacterial pathogens often use specialized molecular syringes, known as type III secretion systems, to inject effector proteins directly into host cells and manipulate immune defenses. Edwardsiella piscicida is a significant pathogen affecting aquaculture and human health, known for triggering inflammation, though the precise bacterial factors driving this response have remained unclear. In this study, we identify the secreted bacterial effector EseJ as a central driver of host inflammatory signaling. We demonstrate that EseJ functions through a dual-action mechanism, using two distinct structural regions to hijack host ubiquitin pathways and overactivate the immune regulator NF-κB. Specifically, EseJ stabilizes the key signaling protein TAK1 while simultaneously protecting the transcription factor p65 from degradation, leading to sustained production of pro-inflammatory cytokines. Disruption of EseJ reduces inflammation during infection in zebrafish models, confirming its critical role in vivo. Because EseJ is highly conserved across Edwardsiella species, our findings reveal an underappreciated strategy used by these pathogens to exacerbate host inflammation, offering new insights into bacterial virulence and potential therapeutic targets for combating infection.
SN - 1553-7374
ER -