Abstract
SummaryThe SPI-2 type III secretion system (T3SS) of intracellular Salmonella enterica translocates effector proteins into mammalian cells. Infection of antigen-presenting cells results in SPI-2 T3SS-dependent ubiquitination and reduction of surface-localized mature MHC class II (mMHCII). We identify the effector SteD as required and sufficient for this process. In Mel Juso cells, SteD localized to the Golgi network and vesicles containing the E3 ubiquitin ligase MARCH8 and mMHCII. SteD caused MARCH8-dependent ubiquitination and depletion of surface mMHCII. One of two transmembrane domains and the C-terminal cytoplasmic region of SteD mediated binding to MARCH8 and mMHCII, respectively. Infection of dendritic cells resulted in SteD-dependent depletion of surface MHCII, the co-stimulatory molecule B7.2, and suppression of T cell activation. SteD also accounted for suppression of T cell activation during Salmonella infection of mice. We propose that SteD is an adaptor, forcing inappropriate ubiquitination of mMHCII by MARCH8 and thereby suppressing T cell activation.
Highlights
Major histocompatibility complex class II (MHCII) molecules have a pivotal function in adaptive immunity by displaying antigenic peptides on the surface of antigen-presenting cells such as dendritic cells (DCs) to CD4-restricted T cells, leading to their activation, proliferation, and differentiation
SteD Reduces Surface Levels of mature MHCII (mMHCII) To identify Salmonella SPI-2 T3SS effector(s) involved in the removal of mMHCII molecules from the surface of infected cells, we used a collection of mCherry-expressing mutant strains lacking individual SPI-2 T3SS effectors to infect human Mel Juso cells
The surface levels of mMHCII in cells infected with the DsifA/DsopD2 mutant were similar to those caused by the WT strain, suggesting that the effect of the DsifA mutant is likely to be indirect, resulting from loss of the vacuolar membrane
Summary
Major histocompatibility complex class II (MHCII) molecules have a pivotal function in adaptive immunity by displaying antigenic peptides on the surface of antigen-presenting cells such as dendritic cells (DCs) to CD4-restricted T cells, leading to their activation, proliferation, and differentiation. MHCII complexes consist of heterodimers of a and b chains that assemble in the endoplasmic reticulum (ER) along with the chaperone invariant chain (Ii) to form a larger structure called the immature MHCII complex (Ii-MHCII). This complex migrates through the Golgi network to the plasma membrane and a late endosomal MHCII compartment, where Ii is degraded by lysosomal proteases, leaving the CLIP peptide in the MHCII peptidebinding groove of the a/b heterodimer. Class II related chaperones HLA-DM and HLA-DO exchange CLIP for antigenic peptides to form mature MHCII (mMHCII) complexes These are transported to the cell surface for antigen presentation (Neefjes et al, 2011). Activation of DCs is accompanied by reduced expression of MARCH1, enabling internalized mMHCII to recycle back to the plasma membrane (De Gassart et al, 2008)
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