期刊
ACS NANO
卷 10, 期 1, 页码 524-538出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.5b05524
关键词
S-glutathionylation; nanotoxicology; macrophage; oxidative stress; redox proteomics; resin-assisted enrichment; immune functions
类别
资金
- NIH [DP2OD006668, UC4 DK104167, U19 ES019544, P41 GM103493, U24-CA-160019]
- DOE
- DOE/BER
- DOE [DE-AC05-76RL0 1830]
- NATIONAL CANCER INSTITUTE [U24CA160019] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [UC4DK104167] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [U19ES019544] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103493] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP2OD006668] Funding Source: NIH RePORTER
Engineered nanoparticles (ENPs) are increasingly utilized for commercial and medical applications; thus, understanding their potential adverse effects is an important societal issue. Herein, we investigated protein S-glutathionylation (SSG) as an underlying regulatory mechanism by which ENPs may alter macrophage innate immune functions, using a quantitative redox proteomics approach for site-specific measurement of SSG modifications. Three high-volume production ENPs (SiO2, Fe3O4, and CoO) were selected as representatives which induce low, moderate, and high propensity, respectively, to stimulate cellular reactive oxygen species (ROS) and disrupt macrophage function. The SSG modifications identified highlighted a broad set of redox sensitive proteins and specific Cys residues which correlated well with the overall level of cellular redox stress and impairment of macrophage phagocytic function (CoO > Fe3O4 >> SiO2). Moreover, our data revealed pathway-specific differences in susceptibility to SSG between ENPs which induce moderate versus high levels of ROS. Pathways regulating protein translation and protein stability indicative of ER stress responses and proteins involved in phagocytosis were among the most sensitive to SSG in response to ENPs that induce subcytoxic levels of redox stress. At higher levels of redox stress, the pattern of SSG modifications displayed reduced specificity and a broader set pathways involving classical stress responses and mitochondrial energetics (e.g., glycolysis) associated with apoptotic mechanisms. An important role for SSG in regulation of macrophage innate immune function was also confirmed by RNA silencing of glutaredoxin, a major enzyme which reverses SSG modifications. Our results provide unique insights into the protein signatures and pathways that serve as ROS sensors and may facilitate cellular adaption to ENPs, versus intracellular targets of ENP-induced oxidative stress that are linked to irreversible cell outcomes.
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