Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1

Joseph E. Qualls, Chitra Subramanian, Wasiulla Rafi, Amber M. Smith, Liza Balouzian, Ashley A. Defreitas, Kari Ann Shirey, Benjamin Reutterer, Elisabeth Kernbauer, Silvia Stockinger, Thomas Decker, Isao Miyairi, Stefanie N. Vogel, Padmini Salgame, Charles O. Rock, Peter J. Murray

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)313-323
Number of pages11
JournalCell Host and Microbe
Volume12
Issue number3
DOIs
StatePublished - Sep 13 2012

Fingerprint

Argininosuccinate Synthase
Citrulline
Infection Control
Nitric Oxide
Arginine
Argininosuccinate Lyase
Macrophages
Recycling
Mycobacterium Infections

All Science Journal Classification (ASJC) codes

  • Virology
  • Parasitology
  • Microbiology

Cite this

Qualls, J. E., Subramanian, C., Rafi, W., Smith, A. M., Balouzian, L., Defreitas, A. A., ... Murray, P. J. (2012). Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host and Microbe, 12(3), 313-323. https://doi.org/10.1016/j.chom.2012.07.012
Qualls, Joseph E. ; Subramanian, Chitra ; Rafi, Wasiulla ; Smith, Amber M. ; Balouzian, Liza ; Defreitas, Ashley A. ; Shirey, Kari Ann ; Reutterer, Benjamin ; Kernbauer, Elisabeth ; Stockinger, Silvia ; Decker, Thomas ; Miyairi, Isao ; Vogel, Stefanie N. ; Salgame, Padmini ; Rock, Charles O. ; Murray, Peter J. / Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. In: Cell Host and Microbe. 2012 ; Vol. 12, No. 3. pp. 313-323.
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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.",
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Qualls, JE, Subramanian, C, Rafi, W, Smith, AM, Balouzian, L, Defreitas, AA, Shirey, KA, Reutterer, B, Kernbauer, E, Stockinger, S, Decker, T, Miyairi, I, Vogel, SN, Salgame, P, Rock, CO & Murray, PJ 2012, 'Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1', Cell Host and Microbe, vol. 12, no. 3, pp. 313-323. https://doi.org/10.1016/j.chom.2012.07.012

Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. / Qualls, Joseph E.; Subramanian, Chitra; Rafi, Wasiulla; Smith, Amber M.; Balouzian, Liza; Defreitas, Ashley A.; Shirey, Kari Ann; Reutterer, Benjamin; Kernbauer, Elisabeth; Stockinger, Silvia; Decker, Thomas; Miyairi, Isao; Vogel, Stefanie N.; Salgame, Padmini; Rock, Charles O.; Murray, Peter J.

In: Cell Host and Microbe, Vol. 12, No. 3, 13.09.2012, p. 313-323.

Research output: Contribution to journalArticle

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T1 - Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1

AU - Qualls, Joseph E.

AU - Subramanian, Chitra

AU - Rafi, Wasiulla

AU - Smith, Amber M.

AU - Balouzian, Liza

AU - Defreitas, Ashley A.

AU - Shirey, Kari Ann

AU - Reutterer, Benjamin

AU - Kernbauer, Elisabeth

AU - Stockinger, Silvia

AU - Decker, Thomas

AU - Miyairi, Isao

AU - Vogel, Stefanie N.

AU - Salgame, Padmini

AU - Rock, Charles O.

AU - Murray, Peter J.

PY - 2012/9/13

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N2 - 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.

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