Asparagine deprivation mediated by Salmonella asparaginase causes suppression of activation-induced T cell metabolic reprogramming.
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.
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
AnnMarie
A
Torres
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Joanna D
JD
Luke
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Amy L
AL
Kullas
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Kanishk
K
Kapilashrami
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Yair
Y
Botbol
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Antonius
A
Koller
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Peter J
PJ
Tonge
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Emily I
EI
Chen
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Fernando
F
Macian
*Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, Graduate Program in Genetics, Department of Chemistry and Institute for Chemical Biology and Drug Discovery, Proteomics Center, and Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York, USA; and Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA a.vandervelden@stonybrook.edu.
Adrianus W M
AW
van der Velden
D000595:Amino Acid Sequence; D000818:Animals; D001215:Asparaginase / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001216:Asparagine / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D016259:Genes, myc; D057131:Immune Evasion / Q000235:genetics / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D019344:Lactic Acid / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014774:Virulence
D001426:Bacterial Proteins; D007376:Interleukin-2; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019344:Lactic Acid; D001216:Asparagine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001215:Asparaginase
T-lymphocyte; bacteria; host; inhibition; pathogen