Shigella IpaH0722 E3 Ubiquitin Ligase Effector Targets TRAF2 to Inhibit PKC–NF-κB Activity in Invaded Epithelial Cells

Abstract

NF-κB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-κB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-κB signaling pathway. Here, we show the inhibition of the NF-κB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-κB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation.

Author Summary

In response to bacterial infection, host cells induce a plethora of innate immune responses to combat the infection. However, many bacterial pathogens have developed sophisticated mechanisms to evade the host's immune system. Because NF-κB is crucial for innate immune responses against bacterial infection, bacterial pathogens deploy multiple countermeasures to inhibit NF-κB activation. The invasion and replication of Shigella within host cells results in cellular damage and the production of bacterial components that trigger NF-κB activation. Here, we show that the Shigella type III secretion system (T3SS) effector IpaH0722, a member of the IpaH E3 ubiquitin ligase family, inhibits NF-κB activation during Shigella infection. IpaH0722 preferentially targets the PKC–NF-κB pathway, which is activated in response to danger signals caused by disruption of the phagosomal membrane during the dissemination of Shigella into the cytoplasm. IpaH0722 inhibits NF-κB activation by targeting TRAF2, which lies downstream of PKC, for ubiquitination and proteasome-dependent degradation.