Abstract
SummaryThe Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII β chain. Here, through a genome-wide mutant screen of human antigen-presenting cells, we show that the NEDD4 family HECT E3 ubiquitin ligase WWP2 and a tumor-suppressing transmembrane protein of unknown biochemical function, TMEM127, are required for SteD-dependent ubiquitination of mMHCII. Although evidently not involved in normal regulation of mMHCII, TMEM127 was essential for SteD to suppress both mMHCII antigen presentation in mouse dendritic cells and MHCII-dependent CD4+ T cell activation. We found that TMEM127 contains a canonical PPxY motif, which was required for binding to WWP2. SteD bound to TMEM127 and enabled TMEM127 to interact with and induce ubiquitination of mature MHCII. Furthermore, SteD also underwent TMEM127- and WWP2-dependent ubiquitination, which both contributed to its degradation and augmented its activity on mMHCII.
Highlights
The ability of Salmonella enterica to cause life-threatening diseases such as typhoid fever requires many bacterial virulence proteins that interfere with both innate and adaptive immune responses, both of which are normally involved in the control and elimination of the pathogen
We showed previously that the highly conserved Salmonella pathogenicity island (SPI)-2 T3SS effector SteD (Jennings et al, 2017) is required and sufficient for this process and used the MHCII-expressing Mel Juso cell line to implicate the MARCH1 homologue, MARCH8, in SteD-dependent ubiquitination of the DRb chain of mature MHC class II (mMHCII) (Bayer-Santos et al, 2016)
Having no detectable influence on the normal regulation of MHCII, we found that TMEM127 is essential for SteD to suppress both mMHCII antigen presentation in dendritic cells and MHCII-dependent CD4+ T cell activation
Summary
The ability of Salmonella enterica to cause life-threatening diseases such as typhoid fever requires many bacterial virulence proteins (effectors) that interfere with both innate and adaptive immune responses, both of which are normally involved in the control and elimination of the pathogen. Innate responses are countered by Salmonella effectors that are translocated into infected host cells (including epithelial cells, macrophages, and dendritic cells [DCs]) by the Salmonella pathogenicity island (SPI)-1 and SPI-2 type III secretion systems (T3SS). These effectors are frequently enzymes that catalyze post-translational modification of host innate signalling pathway proteins (Jennings et al, 2017). DCs internalise Salmonella cells at the gut epithelium and transport them to mesenteric lymph nodes, where T cell responses are initiated (Cerny and Holden, 2019)
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