The Salmonella transmembrane effector SteD hijacks AP1-mediated vesicular trafficking for delivery to antigen-loading MHCII compartments

SteD is a transmembrane effector of the Salmonella SPI-2 type III secretion system that inhibits T cell activation by reducing the amounts of at least three proteins -major histocompatibility complex II (MHCII), CD86 and CD97 -from the surface of antigen-presenting cells. SteD specifically localises at the trans-Golgi network (TGN) and MHCII compartments; however, the targeting, membrane integration and trafficking of SteD are not understood. Using systematic mutagenesis, we identify distinct regions of SteD that are required for these processes. We show that SteD integrates into membranes of the ER/Golgi through a two-step mechanism of membrane recruitment from the cytoplasm followed by integration. SteD then migrates to and accumulates within the TGN. From here it hijacks the host adaptor protein (AP)1-mediated trafficking pathway from the TGN to MHCII compartments. AP1 binding and post-TGN trafficking require a short sequence in the N-terminal cytoplasmic tail of SteD that resembles the AP1-interacting dileucine sorting signal, but in inverted orientation, suggesting convergent evolution. Author summarySalmonella enterica is an intracellular pathogen that causes a range of diseases from gastroenteritis to systemic typhoid fever. Its pathogenesis relies on virulence proteins known as effectors that are delivered into host cells and modulate host cellular processes. The ability of the Salmonella effector SteD to localise within host MHCII compartment membranes is essential for its function in disrupting the adaptive immune response. Here we show that SteD integrates into membranes of the early secretory pathway through a two-step recruitment and integration mechanism. SteD then behaves like a transmembrane cargo protein and hijacks a post-Golgi vesicular trafficking pathway to reach MHCII compartments. This study highlights the sophistication by which bacterial pathogens interact with host cell biology at the molecular level.

Automated summary

This study explores the targeting, membrane integration, and trafficking mechanisms of the Salmonella effector SteD. SteD integrates into the early secretory pathway membranes through two steps and hijacks a vesicular trafficking pathway to reach MHCII compartments. This research highlights the intricate interaction between bacterial pathogens and host cell biology at the molecular level.