Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1.
Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1.
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DOI：
10.1016/j.chom.2012.07.012
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发表时间：
2012-09-13
影响因子：
30.3
通讯作者：
Murray PJ
中科院分区：
文献类型：
--
作者：
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
一氧化氮（NO）可防御细胞内病原体，但由于细胞和组织毒性，其合成必须受到调节。在感染过程中，巨噬细胞输入细胞外精氨酸来合成 NO，产生副产物瓜氨酸。细胞内积累的瓜氨酸被认为可以促进由精氨基琥珀酸合酶 (Ass1) 和精氨基琥珀酸裂解酶 (Asl) 催化的精氨酸合成，从而导致大量的 NO 产生。相反，我们发现瓜氨酸在 NO 产生的早期阶段从巨噬细胞中输出，并保留 < 2% 通过 Ass1-Asl 途径进行回收。随后，细胞外精氨酸耗尽，Ass1 表达允许巨噬细胞从输入的瓜氨酸合成精氨酸以维持 NO 输出。 Ass1缺陷型巨噬细胞在精氨酸稀缺的情况下无法挽救瓜氨酸，导致它们无法控制分枝杆菌感染。因此，细胞外精氨酸促进活化巨噬细胞快速生成 NO，而通过 Ass1 和 Asl 进行瓜氨酸回收是维持最佳 NO 生成的自动防故障系统。
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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影响因子：
4.4
作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
DOI：
10.1073/pnas.0735876100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Lee, J;Ryu, H;Ratan, RR
通讯作者：
Ratan, RR
影响因子：
4.4
作者：
Miyairi, Isao;Tatireddigari, Venkat R. R. Arva;Byrne, Gerald I.
通讯作者：
Byrne, Gerald I.
影响因子：
3.2
作者：
Moeller, Marlo;Nebel, Almut;Hoal, Eileen G.
通讯作者：
Hoal, Eileen G.
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan