The Electrophile Responsive Proteome: Integrating Proteomics and Lipidomics with Cellular Function

Abstract

Significance: The process of lipid peroxidation is emerging as an important mechanism that mediates the posttranslational modification of proteins. Through advanced analytical techniques, lipidomics is now emerging as a critical factor in our understanding of the pathology of a broad range of diseases. Recent Advances: During enzymatic or nonenzymatic lipid peroxidation, the simple structure of an unsaturated fatty acid is converted to an oxylipidome, many members of which are electrophilic and form the reactive lipid species (RLS). This aspect of lipid biology is particularly important, as it directly connects lipidomics with proteomics through the posttranslational modification of a sub-proteome in the cell. This arises, because the electrophilic members of the oxylipidome react with proteins at nucleophilic amino-acid residues and so change their structure and function to form electrophile-responsive proteomes (ERP). Critical Issues: Biological systems have relatively few but well-defined and mechanistically distinct pro-oxidant pathways generating RLS. Defining the ERPs and the mechanisms underlying their formation and action has been a major focus for the field of lipidomics and redox signaling. Future Directions: We propose that a unique oxylipidome can be defined for specific oxidants and will predict the biological responses through the reaction with proteins to form a specific ERP. In this review, we will describe the ERPs that modulate antioxidant and anti-inflammatory protective pathways, including the activation of Keap1/Nrf2 and the promotion of cell death through interactions with mitochondria. Antioxid. Redox Signal. 17, 1580-1589.

Preparation for oxidative stress under hypoxia and metabolic depression: Revisiting the proposal two decades later

“…Although the exact mechanism remains unclear, Kansanen and co-workers (Kansanen et al, 2012) suggest that HNE covalently modifies specific cysteine residues in the Keap1 domain (Kansanen et al, 2012). These modifications decrease the affinity between Keap1 and Nrf2, which allows Nrf2 translocation to the nucleus where it activates the antioxidant response (Higdon et al, 2012;Kansanen et al, 2012). Moreover, treatment with oxidized LDL also led to an activation of Nrf2 pathway, corroborating the finding that lipid peroxidation products modulate antioxidant response (Ishii et al, 2004).…”

“…These molecules, such as HNE, may play a pivotal role in triggering the antioxidant defense in organisms. Some reports show that HNE can react with amino acid residues in the Keap1-Nrf2 complex, modulating its activity (Higdon et al, 2012;Kansanen et al, 2012). Although the exact mechanism remains unclear, Kansanen and co-workers (Kansanen et al, 2012) suggest that HNE covalently modifies specific cysteine residues in the Keap1 domain (Kansanen et al, 2012).…”

Conjugation of Glutathione to Oxidized Tyrosine Residues in Peptides and Proteins

“…Analogous adducts are formed between protein thiols and other electrophiles such as 4-hydroxynonenal (27)(28)(29), and susceptible targets have been identified in proteomic studies (30,31). One example is the Cys residues of KEAP1, which readily undergoes electrophilic addition.…”

From the Editor’s Desk, Editor’s Highlights, Letters to the Editor

“…The challenge for O'Toole et al, and toxicologist in general is to relate toxicant-induced cell-or biochemical-level changes to a molecular mechanism that is consistent with the known chemistry of that toxicant. Accordingly, we suggest that acrolein selectively reacts with a cysteine-directed, electrophile responsive proteome in endothelial cells (Higdon et al, 2012) and that subsequent inhibition of component proteins mediates toxicity that includes either primary or secondary changes in let-7a expression. O'Toole et al correctly recognized the possible causative role of environmental acrolein in pathological processes that involve dysfunctional endothelium (eg, atherosclerosis).…”