title: Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1.
abstract: Nitric oxide (NO) defends against intracellular pathogens, but its synthesis must be regulated due to cell and tissue toxicity. During infection, macrophages import extracellular arginine to synthesize NO, generating the byproduct citrulline. Accumulated intracellular citrulline is thought to fuel arginine synthesis catalyzed by argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl), which would lead to abundant NO production. Instead, we find that citrulline is exported from macrophages during early stages of NO production with <2% retained for recycling via the Ass1-Asl pathway. Later, extracellular arginine is depleted, and Ass1 expression allows macrophages to synthesize arginine from imported citrulline to sustain NO output. Ass1-deficient macrophages fail to salvage citrulline in arginine-scarce conditions, leading to their inability to control mycobacteria infection. Thus, extracellular arginine fuels rapid NO production in activated macrophages, and citrulline recycling via Ass1 and Asl is a fail-safe system that sustains optimum NO production.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Qualls
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.forename: Wasiulla
authors.initials: W
authors.lastname: Rafi
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.forename: Liza
authors.initials: L
authors.lastname: Balouzian
authors.forename: Ashley A
authors.initials: AA
authors.lastname: DeFreitas
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reutterer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kernbauer
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Isao
authors.initials: I
authors.lastname: Miyairi
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Padmini
authors.initials: P
authors.lastname: Salgame
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D001124:Argininosuccinate Synthase