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The discovery and molecular mechanism of the subversion of human E3 ligase RNF213 by the Shigella effector IpaH1.4

ABSTRACT: Ubiquitination plays vital roles in modulating pathogen-host cell interactions. RNF213, a unique 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 Shigella 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 Shigella 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 vitro and 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 function asaays demonstrate that the targeting of host RNF213 by IpaH1.4 promotes Shigella flexneri proliferation within infected cells. In summary, our work uncovers a novel strategy employed by Shigella flexneri to subvert the key host immune factor RNF213, thereby facilitating bacterial proliferation during invasion.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lifeng Pan

PROVIDER: PXD060669 | iProX | Tue Feb 11 00:00:00 GMT 2025

REPOSITORIES: iProX

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