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Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation.

ABSTRACT: The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all NRF2 inducers are electrophilic molecules that possess unwanted off-target effects due to their reactive nature. Here, we report a group of NRF2 inducers, ent-kaurane diterpenoid geopyxins, with and without C151 reactive electrophilic moieties. Among 16 geopyxins, geopyxin F, a non-electrophilic NRF2 activator, showed enhanced cellular protection relative to an electrophilic NRF2 activator, geopyxin C. To our knowledge, this is the first detailed structure-activity relationship study of covalent versus non-covalent NRF2 activators, showing the promise of non-covalent NRF2 activators as potential therapeutic compounds.

SUBMITTER: Liu P

PROVIDER: S-EPMC6800637 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation.

Liu Pengfei P Tian Wang W Tao Shasha S Tillotson Joseph J Wijeratne E M Kithsiri EMK Gunatilaka A A Leslie AAL Zhang Donna D DD Chapman Eli E

Cell chemical biology 20190808 10

The transcription factor NRF2 confers cellular protection by maintaining cellular redox homeostasis and proteostasis. Basal NRF2 levels are normally low due to KEAP1-mediated ubiquitylation and subsequent proteasomal degradation. KEAP1, a substrate adaptor protein of a KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, contains a critical cysteine (C151) that is modified by electrophiles or oxidants, resulting in inactivation of the E3 ligase and inhibition of NRF2 degradation. Currently, nearly all N ...[more]

PMID: 31402317

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Project description:OBJECTIVE:Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS:We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Ppar?/Ppar?) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Ppar?/Ppar? genes (downstream effectors of Stat6). Palmitic acid (PA) and ?-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS:Profiling of genes regulated by Il-4 or Ppar?/Ppar? agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Ppar?/Ppar? increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Ppar?/?-/- macrophages. In concert, ?-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Ppar?/?-/- or Stat6-/- mice. CONCLUSIONS:Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.

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Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation.

Publications

Non-covalent NRF2 Activation Confers Greater Cellular Protection than Covalent Activation.

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