Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses
| Autor: | Youxiang Mao, Di Shi, Gen Li, Peng Jiang |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Inflammation
Mice Knockout Macrophages Cell Biology Argininosuccinate Synthase Janus Kinase 2 Macrophage Activation Listeria monocytogenes Immunity Innate Mice Inbred C57BL Disease Models Animal Mice HEK293 Cells RAW 264.7 Cells STAT1 Transcription Factor Animals Citrulline Humans Listeriosis Inflammation Mediators Phosphorylation Molecular Biology Signal Transduction |
| Zdroj: | Molecular Cell. 82:527-541.e7 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2021.12.006 |
| Popis: | Citrulline can be converted into argininosuccinate by argininosuccinate synthetase (ASS1) in the urea cycle and the citrulline-nitric oxide cycle. However, the regulation and biological function of citrulline metabolism remain obscure in the immune system. Unexpectedly, we found that macrophage citrulline declines rapidly after interferon gamma (IFN-γ) and/or lipopolysaccharide (LPS) stimulation, which is required for efficient proinflammatory signaling activation. Mechanistically, IFN-γ and/or LPS stimulation promotes signal transducers and activators of transcription 1 (STAT1)-mediated ASS1 transcription and Janus kinase2 (JAK2)-mediated phosphorylation of ASS1 at tyrosine 87, thereby leading to citrulline depletion. Reciprocally, increased citrulline directly binds to JAK2 and inhibits JAK2-STAT1 signaling. Blockage of ASS1-mediated citrulline depletion suppresses the host defense against bacterial infection in vivo. We therefore define a central role for ASS1 in controlling inflammatory macrophage activation and antibacterial defense through depletion of cellular citrulline and, further, identify citrulline as an innate immune-signaling metabolite that engages a metabolic checkpoint for proinflammatory responses. |
| Databáze: | OpenAIRE |
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