The Salmonella Effector SteD Mediates MARCH8-Dependent Ubiquitination of MHC II Molecules and Inhibits T Cell Activation.
The 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.
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Ethel
E
Bayer-Santos
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Charlotte H
CH
Durkin
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Luciano A
LA
Rigano
Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany; Centre for Biosecurity and Tropical Infectious Diseases, Australian Institute of Tropical Health and Medicine, James Cook University, McGregor Road, Cairns, QLD 4878, Australia.
Andreas
A
Kupz
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Eric
E
Alix
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Ondrej
O
Cerny
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Elliott
E
Jennings
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Mei
M
Liu
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Aindrias S
AS
Ryan
INRA, UMR 1319 Micalis, Domaine de Vilvert, Jouy-en-Josas 78352, France; AgroParisTech, UMR Micalis, Jouy-en-Josas 78350, France.
Nicolas
N
Lapaque
Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Stefan H E
SHE
Kaufmann
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK. Electronic address: d.holden@imperial.ac.uk.
David W
DW
Holden
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008213:Lymphocyte Activation; D051379:Mice; D011485:Protein Binding; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D001426:Bacterial Proteins; D000949:Histocompatibility Antigens Class II; C000622320:SteD protein, Salmonella typhimurium; C568898:MARCHF8 protein, human; D044767:Ubiquitin-Protein Ligases
Salmonella; dendritic cells; effector; ligase; major histocompatibility complex; ubiquitin