Shigella effector IpaH1.4 subverts host E3 ligase RNF213 to evade antibacterial immunity

Xindi Zhou, Huijing Zhang, Yaru Wang, Danni Wang, Zhiqiao Lin, Yuchao Zhang, Yubin Tang, Jianping Liu, Yu-Feng Yao (), Yixiao Zhang () and Lifeng Pan ()
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Xindi Zhou: Chinese Academy of Sciences
Huijing Zhang: Chinese Academy of Sciences
Yaru Wang: Chinese Academy of Sciences
Danni Wang: Shanghai Jiao Tong University School of Medicine
Zhiqiao Lin: Chinese Academy of Sciences
Yuchao Zhang: Chinese Academy of Sciences
Yubin Tang: Chinese Academy of Sciences
Jianping Liu: Chinese Academy of Sciences
Yu-Feng Yao: Shanghai Jiao Tong University School of Medicine
Yixiao Zhang: Chinese Academy of Sciences
Lifeng Pan: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Ubiquitination plays vital roles in modulating pathogen-host cell interactions. RNF213, a E3 ligase, can catalyze the ubiquitination of lipopolysaccharide (LPS) and is crucial for antibacterial immunity in mammals. Shigella flexneri, an LPS-containing pathogenic bacterium, has developed mechanisms to evade host antibacterial defenses during infection. However, the precise strategies by which S. flexneri circumvents RNF213-mediated antibacterial immunity remain poorly understood. Here, through comprehensive biochemical, structural and cellular analyses, we reveal that the E3 effector IpaH1.4 of S. flexneri can directly target human RNF213 via a specific interaction between the IpaH1.4 LRR domain and the RING domain of RNF213, and mediate the ubiquitination and proteasomal degradation of RNF213 in cells. Furthermore, we determine the cryo-EM structure of human RNF213 and the crystal structure of the IpaH1.4 LRR/RNF213 RING complex, elucidating the molecular mechanism underlying the specific recognition of RNF213 by IpaH1.4. Finally, our cell based functional assays demonstrate that the targeting of host RNF213 by IpaH1.4 promotes S. flexneri proliferation within infected cells. In summary, our work uncovers an unprecedented strategy employed by S. flexneri to subvert the key host immune factor RNF213, thereby facilitating bacterial proliferation during invasion.

Date: 2025
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DOI: 10.1038/s41467-025-58432-y

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