Research ArticleImmunology

Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO

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Science Signaling  12 Feb 2019:
Vol. 12, Issue 568, eaar5926
DOI: 10.1126/scisignal.aar5926

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Mitochondrial ROS in proinflammatory signaling

In addition to releasing proinflammatory cytokines that orchestrate immune responses to pathogens, macrophages also generate reactive oxygen species (ROS) that directly target the pathogen and specific host signaling pathways. Herb et al. found that infection with Listeria monocytogenes caused mouse macrophages to generate mitochondrial ROS (mtROS) that entered the cytosol and induced the formation of intermolecular disulfide bonds in nuclear factor κB (NF-κB) essential modulator (NEMO), a component of the inhibitor of κB kinase (IKK) complex. This covalent linkage of NEMO was required for activation of the ERK1/2 and NF-κB pathways and for the subsequent secretion of proinflammatory cytokines. Thus, disulfide linkage of NEMO is critical for activation of the IKK complex and can be triggered by the infection-induced production of mtROS.

Abstract

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 κB (IκB) kinase (IKK) complex regulatory subunit NEMO [nuclear factor κB (NF-κB) essential modulator] as a target for mtROS. Specifically, mtROS induced intermolecular covalent linkage of NEMO through disulfide bonds formed by Cys54 and Cys347, 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-κB 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.

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