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

NF-κB (nuclear factor B) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IB kinase) complex and by IBα 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.