Modulation of host cell processes by bacterial effector proteins is often referred to as a key virulence factor upon infection. By injecting these effector proteins directly into the cytoplasm of the host cell via the type 3 secretion (T3SS) Gram-negative bacteria can alter induced immue responses to their benefit.

Interestingly, previous reports could identify some, usually T3SS delivered proteins, to have the ability to translocate autonomously into eukaryotic cells such as the Yersinia outer protein M (YopM), being able to inhibit caspase 1 and thus promote Yersinia infection. Moreover, sequence analysis revealed a species-spanning family of effector proteins bearing strong homologies in protein structure and function including candidates from Yersinia, Salmonella and Shigella.

Another LPX-effector-family member is the Shigella effector protein IpaH7.8. By recombinantly expressing and purifying the protein we could show a T3SS-independent, endosomal uptake of IpaH7.8, mediated by two highly-conserved N-terminal α-helices. The latter could also be shown to facilitate an endosomal escape and thus, access to the cytoplasm. To eventually modulate the host's immune response, the well-conserved C-terminal domain of IpaH7.8, comprising an E3 ubiquitin ligase activity, allows hijacking the ubiquitination system of the host. To asses affected target proteins in human macrophages, we conducted a comparative signalotome and ubiquitome analysis upon treatment of THP-1 derived macrophages, revealing potential interaction partners of IpaH7.8. With regard to the anti-inflammatory properties of other LPX effector proteins, the impact of the ubiquitination of target proteins is currently investigated and may allow a therapeutic application of IpaH7.8 to combat inflammatory diseases.