TY - JOUR
T1 - Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming
AU - Torres, Annmarie
AU - Luke, Joanna D.
AU - Kullas, Amy L.
AU - Kapilashrami, Kanishk
AU - Botbol, Yair
AU - Koller, Antonius
AU - Tonge, Peter J.
AU - Chen, Emily I.
AU - Macian, Fernando
AU - van der Velden, Adrianus W.M.
N1 - Publisher Copyright:
© Society for Leukocyte Biology.
PY - 2016/2
Y1 - 2016/2
N2 - Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II L-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which L-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.
AB - Salmonellae are pathogenic bacteria that induce immunosuppression by mechanisms that remain largely unknown. Previously, we showed that a putative type II L-asparaginase produced by Salmonella Typhimurium inhibits T cell responses and mediates virulence in a murine model of infection. Here, we report that this putative L-asparaginase exhibits L-asparagine hydrolase activity required for Salmonella Typhimurium to inhibit T cells. We show that L-asparagine is a nutrient important for T cell activation and that L-asparagine deprivation, such as that mediated by the Salmonella Typhimurium L-asparaginase, causes suppression of activation-induced mammalian target of rapamycin signaling, autophagy, Myc expression, and L-lactate secretion. We also show that L-asparagine deprivation mediated by the Salmonella Typhimurium L-asparaginase causes suppression of cellular processes and pathways involved in protein synthesis, metabolism, and immune response. Our results advance knowledge of a mechanism used by Salmonella Typhimurium to inhibit T cell responses and mediate virulence, and provide new insights into the prerequisites of T cell activation. We propose a model in which L-asparagine deprivation inhibits T cell exit from quiescence by causing suppression of activation-induced metabolic reprogramming.
KW - Bacteria
KW - Host
KW - Inhibition
KW - Pathogen
KW - T-lymphocyte
UR - http://www.scopus.com/inward/record.url?scp=84957666384&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957666384&partnerID=8YFLogxK
U2 - 10.1189/jlb.4A0615-252R
DO - 10.1189/jlb.4A0615-252R
M3 - Article
C2 - 26497246
AN - SCOPUS:84957666384
SN - 0741-5400
VL - 99
SP - 387
EP - 398
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 2
ER -