LysMD3 is a type II membrane protein without an   role in the response to a range of pathogens

Yokoyama, Christine C.; Baldridge, Megan T.; Leung, Daisy W.; Zhao, Guoyan; Desai, Chandni; Liu, Ta‐Chiang; Diaz-Ochoa, Vladimir E.; Huynh, Jeremy P.; Kimmey, Jacqueline M.; Sennott, Erica L.; Hole, Camaron R.; Idol, Rachel A.; Park, Sunmin; Storek, Kelly M.; Wang, Caihong; Hwang, Seungmin; Milam, Ashley A. Viehmann; Chen, Eric; Kerrinnes, Tobias; Starnbach, Michael N.; Handley, Scott A.; Mysorekar, Indira U.; Allen, Paul M.; Monack, Denise M.; Dinauer, Mary C.; Doering, Tamara L.; Tsolis, Renée M.; Dworkin, Jonathan; Stallings, Christina L.; Amarasinghe, Gaya K.; Micchelli, Craig A.; Virgin, Herbert W.

doi:10.1074/jbc.ra117.001246

Cited by 13 publications

(18 citation statements)

References 89 publications

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“…Mouse LysMD3 is a type II integral membrane protein that colocalizes with the Golgi apparatus (45). mLysMD3-deficient mice exhibit no obvious immune response deficiencies in a number of models of infection and inflammation (45). LysM domains have been best characterized for prokaryotes, bacteriophages, and plants.…”

Section: Discussionmentioning

confidence: 99%

Peptidoglycan Contribution to the B Cell Superantigen Activity of Staphylococcal Protein A

Shi

Willing

Kim

et al. 2021

mBio

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Staphylococcus aureus causes reiterative and chronic persistent infections. This can be explained by the formidable ability of this pathogen to escape immune surveillance mechanisms. Cells of S. aureus display the abundant staphylococcal protein A (SpA). SpA binds to immunoglobulin (Ig) molecules and coats the bacterial surface to prevent phagocytic uptake. SpA also binds and cross-links variable heavy 3 (VH3) idiotype (IgM) B cell receptors, promoting B cell expansion and the secretion of nonspecific VH3-IgM via a mechanism requiring CD4+ T cell help. SpA binding to antibodies is mediated by the N-terminal Ig-binding domains (IgBDs). The so-called region X, uncharacterized LysM domain, and C-terminal LPXTG sorting signal for peptidoglycan attachment complete the linear structure of the protein. Here, we report that both the LysM domain and the LPXTG motif sorting signal are required for the B cell superantigen activity of SpA in a mouse model of infection. SpA molecules purified from staphylococcal cultures are sufficient to exert B cell superantigen activity and promote immunoglobulin secretion as long as they carry intact LysM and LPXTG motif domains with bound peptidoglycan fragments. The LysM domain binds the glycan chains of peptidoglycan fragments, whereas the LPXTG motif is covalently linked to wall peptides lacking glycan. These findings emphasize the complexity of SpA interactions with B cell receptors. IMPORTANCE The LysM domain is found in all kingdoms of life. While their function in mammals is not known, LysM domains of bacteria and their phage parasites are associated with enzymes that cleave or remodel peptidoglycan. Plants recognize microbe-associated molecular patterns such as chitin via receptors endowed with LysM-containing ectodomains. In plants, such receptors play equally important roles in defense and symbiosis signaling. SpA of S. aureus carries a LysM domain that binds glycan strands of peptidoglycan to influence defined B cell responses that divert pathogen-specific adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

Peptidoglycan Contribution to the B Cell Superantigen Activity of Staphylococcal Protein A

Shi

Willing

Kim

et al. 2021

mBio

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“…Molecules exposed on bacterial surfaces elicit innate immune response through pattern recognition receptors, induction of cytokines and apoptosis, as well as activation of antimicrobial activity [61]. In addition, Lys-M domain-containing proteins of the host (e.g., LysMD1, LysMD2, LysMD3, and LysMD4) are assumed to be involved in immune responses against bacterial infection [62, 63]. We also observed interaction of YnhG with several bacterial proteins at early (1 hpi) and late (6 hpi) time points of co-infection with connections to pathogenesis, including StpA and PrgI, suggesting a role of this protein in Salmonella virulence.…”

Section: Discussionmentioning

confidence: 99%

Dual perspective proteomics infectome profiling discoversSalmonellatype III secretion system effector functions in macrophages

Geddes‐McAlister

Sukumaran

Vogt

et al. 2021

Preprint

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Intracellular bacterial pathogens have evolved sophisticated infection strategies, including the release and secretion of virulence factors to interfere with host cell functions and to perturb immune responses. For Salmonella enterica serovar Typhimurium (S. Typhimurium), the type III secretion systems encoded on Salmonella pathogenicity islands (SPI) 1 and 2 mediates invasion of the bacterium into innate immune cells and regulates bacterial replication and survival within the hostile environment of the host, respectively. Here, we explore the temporal and strain-specific dual perspective response of both the host and pathogen during cellular infection via quantitative proteomics. We report time- and pathogenicity island-specific expression and secretion of infection-associated proteins (i.e., SL1344_1263, SL1344_3112, SL1344_1563, and YnhG) and regulated immune response proteins in macrophage, including Cd86, Cd40, Casp4, C3, IL-1?, and Cd69). Through intracellular macrophage and in vivo murine models of infection, we reveal a role in virulence for three of the bacterial proteins (SL1344_1263, SL1344_1563, and YnhG), defining their importance as novel T3SS effectors. We characterize the temporal intra- and extracellular production of the effectors and identify their interaction networks in host cells, representing inhibitory and stimulatory pathways mounted by invading bacterial pathogens.

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“…LysMD3 is a predicted membrane protein that localizes to the Golgi of HeLa cells, but no phenotype could be observed in a LysMD3-deficient mouse model, despite extensive testing (Yokoyama et al . 2018 ). It is interesting to speculate that one or more of these proteins could have a role as a peptidoglycan recognition protein in mammals.…”

Section: Peptidoglycan Detection In Mammalsmentioning

confidence: 99%

Uptake, recognition and responses to peptidoglycan in the mammalian host

Bastos

Wheeler

Boneca

2020

FEMS Microbiology Reviews

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Microbiota, and the plethora of signalling molecules that they generate, are a major driving force that underlies a striking range of inter-individual physioanatomic and behavioural consequences for the host organism. Among the bacterial effectors, one finds peptidoglycan, the major constituent of the bacterial cell surface. In the steady-state, fragments of peptidoglycan are constitutively liberated from bacterial members of the gut microbiota, cross the gut epithelial barrier and enter the host system. The fate of these peptidoglycan fragments, and the outcome for the host, depends on the molecular nature of the peptidoglycan, as well the cellular profile of the recipient tissue, mechanism of cell entry, the expression of specific processing and recognition mechanisms by the cell, and the local immune context. At the target level, physiological processes modulated by peptidoglycan are extremely diverse, ranging from immune activation to small molecule metabolism, autophagy and apoptosis. In this review, we bring together a fragmented body of literature on the kinetics and dynamics of peptidoglycan interactions with the mammalian host, explaining how peptidoglycan functions as a signaling molecule in the host under physiological conditions, how it disseminates within the host, and the cellular responses to peptidoglycan.

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LysMD3 is a type II membrane protein without an role in the response to a range of pathogens

Cited by 13 publications

References 89 publications

Peptidoglycan Contribution to the B Cell Superantigen Activity of Staphylococcal Protein A

Peptidoglycan Contribution to the B Cell Superantigen Activity of Staphylococcal Protein A

Dual perspective proteomics infectome profiling discoversSalmonellatype III secretion system effector functions in macrophages

Uptake, recognition and responses to peptidoglycan in the mammalian host

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