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; Černý, Ondřej; Jennings, Elliott; Mei, Linfeng; Ryan, Aindrias; Lapaque, Nicolas; Kaufmann, Stefan H. E.; Holden, David W.

doi:10.1016/j.chom.2016.10.007

Cited by 86 publications

(117 citation statements)

References 30 publications

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“…SteD STM2139 t0718 (STY2367) SPA0713 Inhibits MHC class II presentation on infected cells, inhibits T cell activation (Bayer-Santos et al, 2016;Niemann et al, 2011) GogB Bacteriophage (Gifsy-1) STM2584 Absent Absent E3 ubiquitin ligase that inhibits NF-κB signalling by inhibiting the activity of host SCF ubiquitin ligase (Pilar, Reid-Yu, Cooper, Mulder, & Coombes, 2012).…”

Section: Sopementioning

confidence: 99%

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TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

Johnson

Mylona

Frankel

2018

Cellular Microbiology

141

106

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Although nontyphoidal Salmonella (NTS; including Salmonella Typhimurium) mainly cause gastroenteritis, typhoidal serovars (Salmonella Typhi and Salmonella Paratyphi A) cause typhoid fever, the treatment of which is threatened by increasing drug resistance. Our understanding of S. Typhi infection in human remains poorly understood, likely due to the host restriction of typhoidal strains and the subsequent popularity of the S. Typhimurium mouse typhoid model. However, translating findings with S. Typhimurium across to S. Typhi has some limitations. Notably, S. Typhi has specific virulence factors, including typhoid toxin and Vi antigen, involved in symptom development and immune evasion, respectively. In addition to unique virulence factors, both typhoidal and NTS rely on two pathogenicity-island encoded type III secretion systems (T3SS), the SPI-1 and SPI-2 T3SS, for invasion and intracellular replication. Marked differences have been observed in terms of T3SS regulation in response to bile, oxygen, and fever-like temperatures. Moreover, approximately half of effectors found in S. Typhimurium are either absent or pseudogenes in S. Typhi, with most of the remaining exhibiting sequence variation. Typhoidal-specific T3SS effectors have also been described. This review discusses what is known about the pathogenesis of typhoidal Salmonella with emphasis on unique behaviours and key differences when compared with S. Typhimurium.

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Section: Sopementioning

confidence: 99%

Section: Sopementioning

confidence: 99%

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

Johnson

Mylona

Frankel

2018

Cellular Microbiology

141

106

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“…Our fluorescence microscopy data rule out gross defects in subcellular localization for Ser-198 mutants, but they do not rule out a role for this position in membrane sub-domain localization. It could further play a role in internal structural stabilization, formation of oligomeric MARCH9 structures (31), or interactions with adaptor proteins that may be required to bring MARCH9 and substrates together in the membrane, the latter being a role recently ascribed to the Salmonella protein SteD in MARCH8mediated MHC-II regulation in infected cells (54). Perhaps most interestingly, Ser-198 may represent the site of a specific interaction with a complementary site that is available in both HLA-A2 and CD4 TM domains.…”

Section: Transmembrane Determinants Of March9 Functionmentioning

confidence: 99%

A serine in the first transmembrane domain of the human E3 ubiquitin ligase MARCH9 is critical for down-regulation of its protein substrates

Tan

Byrne

Ah-Cann

et al. 2019

Journal of Biological Chemistry

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The membrane-associated RING-CH (MARCH) family of membrane-bound E3 ubiquitin ligases regulates the levels of cell-surface membrane proteins, many of which are involved in immune responses. Although their role in ubiquitin-dependent endocytosis and degradation of cell-surface proteins is extensively documented, the features of MARCH proteins and their substrates that drive the molecular recognition events leading to ubiquitin transfer remain poorly defined. In this study, we sought to determine the features of human MARCH9 that are required for regulating the surface levels of its substrate proteins. Consistent with previous studies of other MARCH proteins, we found that susceptibility to MARCH9 activity is encoded in the transmembrane (TM) domains of its substrates. Accordingly, substitutions at specific residues and motifs within MARCH9's TM domains resulted in varying degrees of functional impairment. Most notably, a single serine-to-alanine substitution in the first of its two TM domains rendered MARCH9 completely unable to alter the surface levels of two different substrates: the major histocompatibility class I molecule HLA-A2 and the T-cell coreceptor CD4. Solution NMR analysis of a MARCH9 fragment encompassing the two TM domains and extracellular connecting loop revealed that the residues contributing most to MARCH9 activity are located in the ␣-helical portions of TM1 and TM2 that are closest to the extracellular face of the lipid bilayer. This observation defines a key region required for substrate regulation. In summary, our biochemical and structural findings demonstrate that specific sequences in the ␣-helical MARCH9 TM domains make crucial contributions to its ability to down-regulate its protein substrates.The membrane-associated RING-CH (MARCH) 5 proteins are a family of E3 ubiquitin ligases that regulate the cell-surface expression of proteins with important roles in immunity (1-3). Six mammalian MARCH proteins (MARCH1-4, MARCH8, and MARCH9) share a common structural organization featuring an N-terminal RING-CH domain that facilitates ubiquitin transfer, two predicted transmembrane (TM) domains connected by a short extracellular loop, and a C-terminal cytosolic tail of variable length (1). Biologically, the best characterized member of this family is MARCH1, whose biological roles include targeting major histocompatibility class II (MHC-II) complexes and the T-cell co-stimulatory molecule CD86 (B7.2) to endocytotic vesicles in antigen-presenting cells via ubiquitin-dependent pathways (4 -9). In dendritic cells, when maturation is triggered by the uptake of antigenic cargo and/or exposure to Toll-like receptor ligands, MARCH1 activity is opposed by CD83 expression (10) and MARCH1 transcription stops (9, 11), resulting in MHC-II and CD86 up-regulation at the cell surface and increased CD4 ϩ T-cell stimulatory capacity. A similar role for MARCH8 has recently been identified in thymic epithelial cells (12,13), where it plays a key role in the development of CD4 ϩ T-cells. The dynamic control of MARCH...

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“…These dendritic cells are of particular importance for gastrointestinal infections as they have been shown to sample the gastrointestinal environment, providing an additional mechanism for Salmonellae to transmit the gastrointestinal epithelial barrier (Rescigno et al, 2001). In an effort to block the bridge between innate and adaptive immune systems normally occupied by dendritic cells, Salmonellae will downregulate expression of the MHC class II system that prevents activation and proliferation of Salmonellae-specific T-cells (Cheminay, Möhlenbrink, & Hensel, 2005;Tobar et al, 2006), in some cases via the secreted SteD effector (Bayer-Santos et al, 2016). Salmonellae also inhibit T-cell activity through an L-asparaginase that depletes the L-asparagine required for proper T-cell proliferation (Kullas et al, 2012).…”

Section: Typhimurium Systemic Infection Alison O'brien and Colleaguementioning

confidence: 99%

The cellular microbiology of Salmonellae interactions with macrophages

Petersen

Miller

2019

Cellular Microbiology

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Salmonellae are important enteric pathogens that cause gastroenteritis and systemic illnesses. Macrophages are important components of both the innate and acquired immune system, acting as phagocytes with significant antimicrobial killing activities that present antigen to the adaptive immune system. Macrophages can also be cultured from a variety of sites as primary cells, and the study of the survival and interactions of Salmonellae with these cells is a very early model of infection and cellular microbiology. This review traces the history of discoveries made using Salmonellae infection of macrophages and addresses the possibility of future research in this area, in particular with regards to understanding the complexity of individual bacteria and macrophage cell variability and how such heterogeneity may alter the outcome of infection.

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The Salmonella Effector SteD Mediates MARCH8-Dependent Ubiquitination of MHC II Molecules and Inhibits T Cell Activation

Cited by 86 publications

References 30 publications

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

A serine in the first transmembrane domain of the human E3 ubiquitin ligase MARCH9 is critical for down-regulation of its protein substrates

The cellular microbiology of Salmonellae interactions with macrophages

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