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Edwardsiella piscicida effector EseD mediates ferritinophagy by targeting NCOA4 and STING in teleost cells.

Jingqi Ren,Linan Chen,Rongchen Ye,Dan Xiong,Zhe Wang,Hong Zhou

Published 2025 in Fish and Shellfish Immunology

ABSTRACT

Edwardsiella piscicida (E. piscicida), an important pathogen in aquatic systems, has been demonstrated to hijack Ncoa4 (nuclear receptor co-activator 4)-dependent ferritinophagy through its type III secretion system effector EseD, thereby promoting intracellular bacterial survival. However, the molecular mechanisms governing EseD-mediated ferritinophagy remain elusive. To address this issue, the lysosomal localization analysis was performed to observe that EseD promoted the Ncoa4 translocation to lysosomes, corroborating the involvement of EseD in ferritinophagy-mediated target protein degradation. Subsequently, by employing co-immunoprecipitation and confocal microscopy, this study revealed that EseD specifically interacted with both Ncoa4 and ferritin, as well as orchestrated the formation of Ncoa4-ferritin complex. These findings provided direct evidence for EseD-induced ferritinophagic flux. Furthermore, it was the first time to characterize the function of stimulator of interferon gene (Sting) as an integral component of the ferritinophagy complex in fish, in which Sting was detected to co-localize with the Ncoa4, ferritin and EseD, suggesting that Sting participated in EseD-induced ferritinophagic complex assembly. Collectively, these data establish a novel pathogenic mechanism where E. piscicida exploits EseD-mediated Ncoa4-ferritin-Sting complex to manipulate host ferritinophagy for intracellular persistence. This work advances our understanding of host-pathogen interactions at the intersection of ferritinophagy, providing new therapeutic targets for controlling E. piscicida infection in aquaculture.

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