Hsp90 Interaction with INrf2(Keap1) Mediates Stress-induced Nrf2 Activation

INrf2(Keap1) functions as an adapter for Cul3/Rbx1-mediated degradation of Nrf2. In response to stress, Nrf2 is released from INrf2 and translocates inside the nucleus leading to activation of cytoprotective proteins critical in protection against adverse effects including cancer. We demonstrate here a novel role of heat shock protein 90 (Hsp90) in control of the INrf2 and Nrf2 activation. Hsp90 interacted with INrf2 that leds to stabilization of INrf2 during heat shock stress. Domain mapping showed the requirement of INrf2-NTR and the Hsp90-CLD region for interaction of Hsp90 with INrf2. Heat shock and antioxidants induced Hsp90, and casein kinase 2 (CK2) phosphorylated INrf2Thr55. This led to increased Hsp90-INrf2 interaction, dissociation of the Rbx1/Cul3·INrf2·Nrf2 complex, and activation of Nrf2. Inhibitors of CK2 and Hsp90, and mutation of INrf2Thr55 abolished the Hsp90-INrf2 interaction and downstream signaling. INrf2 is released from Hsp90 once the heat shock or antioxidant stress subsidized, thereby allowing INrf2 to interact with Nrf2 and facilitate Nrf2 ubiquitination and degradation. The results together demonstrate a novel role for the stress-induced Hsp90-INrf2 interaction in regulation of Nrf2 activation and induction of cytoprotective proteins.     

Marburgvirus Hijacks Nrf2-Dependent Pathway by Targeting Nrf2-Negative Regulator Keap1

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Selenite cataracts: Activation of endoplasmic reticulum stress and loss of Nrf2/Keap1-dependent stress protection

Cataract-induced by sodium selenite in suckling rats is one of the suitable animal models to study the basic mechanism of human cataract formation. The aim of this present investigation is to study the endoplasmic reticulum (ER) stress-mediated activation of unfolded protein response (UPR), overproduction of reactive oxygen species (ROS), and suppression of Nrf2/Keap1-dependent antioxidant protection through endoplasmic reticulum-associated degradation (ERAD) pathway and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with sodium selenite. Lenses enucleated from sodium selenite injected rats generated overproduction of ROS in lens epithelial cells and newly formed lens fiber cells resulting in massive lens epithelial cells death after 1–5 days. All these lenses developed nuclear cataracts after 4–5 days. Sodium selenite treated HLECs induced ER stress and activated the UPR leading to release of Ca^2 + from ER, ROS overproduction and finally HLECs death. Sodium selenite also activated the mRNA expressions of passive DNA demethylation pathway enzymes such as Dnmt1, Dnmt3a, and Dnmt3b, and active DNA demethylation pathway enzyme, Tet1 leading to DNA demethylation in the Keap1 promoter of HLECs. This demethylated Keap1 promoter results in overexpression of Keap1 mRNA and protein. Overexpression Keap1 protein suppresses the Nrf2 protein through ERAD leading to suppression of Nrf2/Keap1 dependent antioxidant protection in the HLECs treated with sodium selenite. As an outcome, the cellular redox status is altered towards lens oxidation and results in cataract formation.     

Activation of Nrf2/Keap1 signaling and autophagy induction against oxidative stress in heart in iron deficiency

We investigated the effects of dietary iron deficiency on the redox system in the heart. Dietary iron deficiency increased heart weight and accumulation of carbonylated proteins. However, expression levels of heme oxygenase-1 and LC3-II, an antioxidant enzyme and an autophagic marker, respectively, in iron-deficient mice were upregulated compared to the control group, resulting in a surrogate phenomenon against oxidative stress.     

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl-bridging group to constrain the peptides, coupled with a glutamic acid to proline replacement leads to a new peptide with a K_i of 6.1?nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity.     

VEGF-R1 as a Potential Molecular Target for Anticancer Therapy

The possibility of using VEGF-R1 receptor for targeted therapy in oncology was investigated. Using the approach to measuring the protein content in intact nuclei of cells, which was developed by us, we showed the presence of this receptor in the nuclei of tumor, but not normal cells. A direct correlation between the level of VEGF-R1 expression in the nucleus and the degree of malignancy of tumor cells, indicating the prognostic value of this parameter, was found. The mechanisms of the functioning of this receptor and the pathways of inhibiting its activity are discussed, and the validity of the selection of VEGF-R1 as a molecular target for anticancer therapy is conformed.     

CKLF1作为缺血性脑卒中治疗的潜在靶点

缺血性脑卒中是一种血液循环障碍疾病,可导致严重的神经功能缺损.卒中病人中约有87％的病例为缺血性卒中.神经炎症是中风损伤的主要病理状态之一.CKLF1是2001年发现的非经典CC型趋化因子,对单核细胞、中性粒细胞和淋巴细胞表现出很强的趋化活性.CKLF1在胎儿大脑中含量最高,但在健康成人阶段不存在.越来越多的证据表明,...