Tweaking the NRF2 signaling cascade in human myelogenous leukemia cells by artificial nanoorganelles

• 成果类型: Article
• 署名作者: Wolf, Konstantin M. P.; Maffeis, Viviana; Schoenenberger, Cora Ann; Zuend, Tamara; Bar-Peled, Liron; Palivan, Cornelia G.; Vogel, Viola
• 署名单位: Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Basel; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9108
• DOI: 10.1073/pnas.2219470121
• 发表日期: 2024-05-28
• 关键词: kappa-b activities; oxidative stress; sensor keap1; activation; polymersomes; degradation; PROTECTION; DYNAMICS; element; ligase

摘要

NRF2 (nuclear factor erythroid - 2 - related factor 2) is a key regulator of genes involved in the cell's protective response to oxidative stress. Upon activation by disturbed redox homeostasis, NRF2 promotes the expression of metabolic enzymes to eliminate reactive oxygen species (ROS). Cell internalization of peroxisome - like artificial organelles that harbor redox - regulating enzymes was previously shown to reduce ROS - induced stress and thus cell death. However, if and to which extent ROS degradation by such nanocompartments interferes with redox signaling pathways is largely unknown. Here, we advance the design of H 2 O 2 - degrading artificial nanoorganelles (AnOs) that exposed surface - attached cell penetrating peptides (CPP) for enhanced uptake and were equipped with a fluorescent moiety for rapid visualization within cells. To investigate how such AnOs integrate in cellular redox signaling, we engineered leukemic K562 cells that report on NRF2 activation by increased mCherry expression. Once internalized, ROS - metabolizing AnOs dampen intracellular NRF2 signaling upon oxidative injury by degrading H 2 O 2 . Moreover, intracellular AnOs conferred protection against ROSinduced cell death in conditions when endogenous ROS - protection mechanisms have been compromised by depletion of glutathione or knockdown of NRF2. We demonstrate CPP - facilitated AnO uptake and AnO - mediated protection against ROS insults also in the T lymphocyte population of primary peripheral blood mononuclear cells from healthy donors. Overall, our data suggest that intracellular AnOs alleviated cellular stress by the on - site reduction of ROS.