| First Author | Herb M | Year | 2019 |
| Journal | Sci Signal | Volume | 12 |
| Issue | 568 | PubMed ID | 30755476 |
| Mgi Jnum | J:281774 | Mgi Id | MGI:6381162 |
| Doi | 10.1126/scisignal.aar5926 | Citation | Herb M, et al. (2019) Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO. Sci Signal 12(568) |
| abstractText | A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in Listeria monocytogenes-infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). We identified the inhibitor of kappaB (IkappaB) kinase (IKK) complex regulatory subunit NEMO [nuclear factor kappaB (NF-kappaB) essential modulator] as a target for mtROS. Specifically, mtROS induced intermolecular covalent linkage of NEMO through disulfide bonds formed by Cys(54) and Cys(347), which was essential for activation of the IKK complex and subsequent signaling through the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and NF-kappaB pathways that eventually led to the secretion of proinflammatory cytokines. We thus identify mtROS-dependent disulfide linkage of NEMO as an essential regulatory step of the proinflammatory response of macrophages to bacterial infection. |
