The Salmonella effector SteD mediates MARCH8-dependent ubiquitination of MHC II molecules and inhibits T cell activation

Bayer-Santos, Ethel, Durkin, Charlotte H., Rigano, Luciano A., Kupz, Andreas, Alix, Eric, Cerny, Ondrej, Jennings, Elliott, Liu, Mei, Ryan, Aindrias S., Lapaque, Nicolas, Kaufmann, Stefan H.E., and Holden, David W. (2016) The Salmonella effector SteD mediates MARCH8-dependent ubiquitination of MHC II molecules and inhibits T cell activation. Cell Host & Microbe, 20 (5). pp. 584-595.

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Abstract

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.

Item ID: 46473
Item Type: Article (Research - C1)
ISSN: 1934-6069
Keywords: Salmonella; dendritic cells; effector; ligase; major histocompatibility complex; ubiquitin
Additional Information:

© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funders: Medical Research Council (MRC), Wellcome Trust (WT), CAPES Fellowship
Projects and Grants: MRC MR/K027077/1, WT 095484/Z/11/Z, CAPES 9236/13-9
Date Deposited: 24 Nov 2016 00:05
FoR Codes: 06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110309 Infectious Diseases @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110707 Innate Immunity @ 20%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 65%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 35%
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