RRC ID 59367
著者 Kosztelnik M, Kurucz A, Papp D, Jones E, Sigmond T, Barna J, Traka MH, Lorincz T, Szarka A, Banhegyi G, Vellai T, Korcsmaros T, Kapuy O.
タイトル Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress.
ジャーナル FASEB J
Abstract NF-E2-related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species-generated oxidative stress. The aim of the present study was to investigate how autophagy is turned off during prolonged oxidative stress, to avoid overeating and destruction of essential cellular components. AMPK is a key cellular energy sensor highly conserved in eukaryotic organisms, and it has an essential role in autophagy activation at various stress events. Here the role of human AMPK and its Caenorhabditis elegans counterpart AAK-2 was explored upon oxidative stress. We investigated the regulatory connection between NRF2 and AMPK during oxidative stress induced by tert-butyl hydroperoxide (TBHP) in HEK293T cells and C. elegans. Putative conserved NRF2/protein skinhead-1 binding sites were found in AMPK/aak-2 genes by in silico analysis and were later confirmed experimentally by using EMSA. After addition of TBHP, NRF2 and AMPK showed a quick activation; AMPK was later down-regulated, however, while NRF2 level remained high. Autophagosome formation and Unc-51-like autophagy activating kinase 1 phosphorylation were initially stimulated, but they returned to basal values after 4 h of TBHP treatment. The silencing of NRF2 resulted in a constant activation of AMPK leading to hyperactivation of autophagy during oxidative stress. We observed the same effects in C. elegans demonstrating the conservation of this self-defense mechanism to save cells from hyperactivated autophagy upon prolonged oxidative stress. We conclude that NRF2 negatively regulates autophagy through delayed down-regulation of the expression of AMPK upon prolonged oxidative stress. This regulatory connection between NRF2 and AMPK may have an important role in understanding how autophagy is regulated in chronic human morbidities characterized by oxidative stress, such as neurodegenerative diseases, certain cancer types, and in metabolic diseases.-Kosztelnik, M., Kurucz, A., Papp, D., Jones, E., Sigmond, T., Barna, J., Traka, M. H., Lorincz, T., Szarka, A., Banhegyi, G., Vellai, T., Korcsmaros, T., Kapuy, O. Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress.
巻・号 33(2)
ページ 2372-2387
公開日 2019-2-1
DOI 10.1096/fj.201800565RR
PMID 30277819
PMC PMC6338645
MeSH AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases Animals Autophagy* Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / antagonists & inhibitors* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Down-Regulation Gene Expression Regulation* HEK293 Cells Humans NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* Oxidation-Reduction Oxidative Stress* Phosphorylation Protein Kinases / chemistry* Protein Kinases / genetics Protein Kinases / metabolism Protein Serine-Threonine Kinases / antagonists & inhibitors* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Transcription Factors / genetics Transcription Factors / metabolism*
IF 5.391
引用数 7
リソース情報
線虫 tm2508