Endogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives

Figure 3

Signaling pathways modulated by electrophilic lipids. (a) Nrf2-dependent antioxidant response. Under basal conditions, Keap1 binds to Nrf2, sending it to proteasomal degradation via cullin-3-dependent ubiquitination. Electrophilic lipids react with target cysteines on Keap1 inhibiting ubiquitination of Nrf2 and promoting nuclear accumulation of Nrf2 which leads to the activation of ARE-dependent genes; (b) Heat shock response. Under basal conditions, inert Hsf1 is found in the cytoplasm bound with Hsp72 and Hsp90. Electrophiles react with Hsp72 and Hsp90 and promote Hsf1 release, phosphorylation, trimerization, and translocation to the nucleus where Hsf1 activates the transcription of heat shock response genes. (c) NF-κB pathway. Under basal conditions, IKK phosphorylates IκB, causing the release of the heterodimer p50/p65 which translocates to the nucleus and activates a variety of proinflammatory mediators. Electrophiles react with IKK leading to kinase inhibition and blocking NF-κB activation. In addition, covalent reaction of electrophiles with target cysteines in the DNA-binding domain of p65 and p50 inhibits their binding to DNA.

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