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Review
.2023 Apr 1;12(4):856.
doi: 10.3390/antiox12040856.

The 4-Hydroxynonenal-Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?

Affiliations
Review

The 4-Hydroxynonenal-Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?

Lidija Milkovic et al. Antioxidants (Basel)..

Abstract

It is well known that oxidative stress and lipid peroxidation (LPO) play a role in physiology and pathology. The most studied LPO product with pleiotropic capabilities is 4-hydroxynonenal (4-HNE). It is considered as an important mediator of cellular signaling processes and a second messenger of reactive oxygen species. The effects of 4-HNE are mainly attributed to its adduction with proteins. Whereas the Michael adducts thus formed are preferred in an order of potency of cysteine > histidine > lysine over Schiff base formation, it is not known which proteins are the preferred targets for 4-HNE under what physiological or pathological conditions. In this review, we briefly discuss the methods used to identify 4-HNE-protein adducts, the progress of mass spectrometry in deciphering the specific protein targets, and their biological relevance, focusing on the role of 4-HNE protein adducts in the adaptive response through modulation of the NRF2/KEAP1 pathway and ferroptosis.

Keywords: 4-HNE–protein adducts; 4-hydroxynonenal (4-HNE); adaptive response; ferroptosis; immunochemical methods; lipid peroxidation; mass spectrometry (MS); the NRF2/KEAP1 signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
4-HNE forms adducts with protein amino acid residues via Michael addition or Schiff’s base formation that are frequently analyzed by immunochemistry, mass spectrometry, or a combination of immunochemistry with mass spectrometry.
Figure 2
Figure 2
Immunohistochemistry with the monoclonal antibody specific for the 4-HNE–His shows the prominent presence of the protein adducts of the aldehyde in connective tissue (brown) below the 4-HNE–His negative epithelium (blue) of esophagus of a healthy rat (left photo 100×) and in the blood vessel (indicated by the yellow arrow). In human colon cancer, 4-HNE can be seen only in the nuclear region of a few cancer cells (right photo 50×). In both cases the presence of 4-HNE–protein adducts is visualized by dark brown di-amino-benzidine staining, with the blue hematoxylin contrast staining.
Figure 3
Figure 3
Activation of NRF2 signaling pathway by 4-HNE. 4-HNE adduction of KEAP1 at Cys513 and Cys518 disrupts the binding of NRF2 to KEAP1 and subsequent proteasomal degradation of NRF2. Instead, accumulated cytoplasmatic NRF2 translocates to the nucleus, initiating the expression of more than 200 genes containing the ARE in their promoter, such as TrxR1. Other cysteine residues in KEAP1, such as Cys151, Cys288, Cys226, and Cys368, have also been suggested to be involved in the activation of the NRF2 signaling pathway. Abbreviations: 4-HNE: 4-hydroxynonenal, ARE: antioxidant response element, BTB: Broad complex, Tramtrack, and Bric-a-Brac domain of KEAP1, Cul3: Cullin 3 E3 ubiquitin ligase, Cys: cysteine, DLG: motif of the Neh2 domain of the NRF2 responsible for direct interaction with KEAP1, ETGE: motif of the Neh2 domain of the NRF2 responsible for direct interaction with KEAP1, KEAP1: kelch-like ECH-associated protein 1, KELCH: Kelch domain of KEAP1, Maf: small Maf proteins, NRF2: nuclear factor erythroid 2-like 2, TrxR1: thioredoxin reductase 1, Ub: ubiquitin.
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References

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