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A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory response

Abstract

NF-κB (nuclear factor κB) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IκB kinase) complex and by IκBα degradation. When Shigella bacteria multiply within epithelial cells they release peptidoglycans, which are recognized by Nod1 and stimulate the NF-κB pathway, thus leading to a severe inflammatory response. Here, we show that IpaH9.8, a Shigella effector possessing E3 ligase activity, dampens the NF-κB-mediated inflammatory response to the bacterial infection in a unique way. IpaH9.8 interacts with NEMO/IKKγ and ABIN-1, a ubiquitin-binding adaptor protein, promoting ABIN-1-dependent polyubiquitylation of NEMO. Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which perturbs NF-κB activation. As NEMO is essential for NF-κB activation, we propose that the polyubiquitylation and degradation of NEMO during Shigella infection is a new bacterial strategy to modulate host inflammatory responses.

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Figure 1: IpaH9.8 inhibits NF-κB activity.
Figure 2: IpaH9.8 promotes NEMO ubiquitylation and degradation.
Figure 4: ABIN-1 promotes IpaH9.8-mediated NEMO ubiquitylation.
Figure 3: IpaH9.8 targets NEMO Lys 309 and Lys 321 residues for ubiquitylation.
Figure 5: ABIN-1 acts as adaptor protein between IpaH9.8 and NEMO.

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Acknowledgements

We thank the members of the Sasakawa laboratory for their advice. This work was supported by Grand-in-Aid for Scientific Research (S) (20229006); a Grand-in-Aid for Exploratory Research (20659067); a Grant-in-Aid for Scientific Research on Priority Areas (18073003); the Strategic Cooperation to Control Emerging and Reemerging Infections Funded by The Special Coordination Funds for Promoting Science and Technology; and a Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST).

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H.A. designed and performed the experiments. M.K. gave advice and designed the experiments. M.S.-S. provided NEMO materials. A.M. provided ABIN-1 materials. M.O. gave advice. C.S. conceived and wrote the paper.

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Correspondence to Chihiro Sasakawa.

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The authors declare no competing financial interests.

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Ashida, H., Kim, M., Schmidt-Supprian, M. et al. A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory response. Nat Cell Biol 12, 66–73 (2010). https://doi.org/10.1038/ncb2006

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