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Title: Quantitative Profiling of Protein S-Glutathionylation Reveals Redox-Dependent Regulation of Macrophage Function During Nanoparticle-Induced Oxidative Stress

Engineered nanoparticles (ENPs) are emerging functional materials increasingly utilized for commercial and medical applications. Due to the potential hazard effects of ENPs to human health, it is significant to assess and understand the underlying mechanisms of nanotoxicity. Here, we investigate protein S-glutathionylation (SSG) as an underlying regulatory mechanism for ENP-induced oxidative stress in macrophages by applying a recently developed quantitative redox proteomics approach for site-specific measurements of SSG. Three high-volume production ENPs (SiO 2, Fe 3O 4 and CoO) were selected as representative ENPs with low, moderate, and high reactive oxygen species (ROS) activity, respectively. Among these nanoparticles, we observe that CoO led to the most significant dose-dependent oxidative stress and increase of protein SSG modifications in macrophages. Our site-specific SSG changes highlighted a broad set of redox sensitive proteins and their specific Cys residues potentially implicated in stress response. Functional analysis revealed that the most significantly enriched functional categories for SSG-modified proteins were stress response, cellular structure change, and cell death or survival. Moreover, ENPs-induce oxidative stress levels (CoO > Fe 3O 4 > SiO 2) were found to correlate well with the levels of impairment of macrophage phagocytic activity and the overall degrees of increases in SSG. RNAmore » silencing knockdown experiment of glutaredoxin 1 (Grx1) also led to a decreased phagocytic activity in macrophages, which suggested a regulatory role of SSG in phagocytosis. Together, the results provided valuable insights of protein SSG as a potential regulatory mechanism in response to nanomaterial-induced oxidative stress and immunity dysfunction.« less
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [3] ;  [1] ;  [1]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division; Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Publication Date:
Report Number(s):
Journal ID: ISSN 1936-0851; 48135; 400412000
Grant/Contract Number:
AC05-76RL01830; DP2OD006668; UC4 DK104167; ES019544; P41 GM103493; U24-CA-160019
Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 1936-0851
American Chemical Society
Research Org:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
77 NANOSCIENCE AND NANOTECHNOLOGY; 60 APPLIED LIFE SCIENCES; S-glutathionylation; nanotoxicology; macrophage; oxidative stress; redox proteomics; resin-assisted enrichment; immune functions; Environmental Molecular Sciences Laboratory
OSTI Identifier: