| First Author | Mao Y | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 3 | Pages | 527-541.e7 |
| PubMed ID | 35016033 | Mgi Jnum | J:326371 |
| Mgi Id | MGI:6874698 | Doi | 10.1016/j.molcel.2021.12.006 |
| Citation | Mao Y, et al. (2022) Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses. Mol Cell 82(3):527-541.e7 |
| abstractText | 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-gamma) and/or lipopolysaccharide (LPS) stimulation, which is required for efficient proinflammatory signaling activation. Mechanistically, IFN-gamma 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. |
