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An Investigation of the Regulatory Relationship of the Keap1/Nrf2/ARE Signaling System and Transcriptional Regulators of Lysosomal Biogenesis

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Abstract

Despite the key role of the Keap1/Nrf2/ARE redox-sensitive signaling system in cell metabolism, almost nothing is known about its association with lysosome biogenesis. In the present work, a theoretical and experimental analysis of the possibility of such a relationship is carried out. By forming a position frequency matrix in the genes of the transcription factors TFEB and TFE3, the presence of a large number of ARE-like sequences in noncoding regions was found. The impact in vitro on J774 cells with activators of the Keap1/Nrf2/ARE system (original synthetic monophenol TS-13 and reference drug tert-butylhydroquinone) leads to dose-dependent induction of Tfe3 and Tfeb genes accompanied by a gradual increase in the number of lysosomes and the intensity of the autophagosome–lysosome fusion. Thus, it can be assumed that proteins controlling ARE-dependent genes can influence lysosomal biogenesis.

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ACKNOWLEDGMENTS

This work was performed using the equipment of the Centers for Collective Use “Modern Optical Systems” and “Proteomic Analysis” and supported by funding from the Russian Ministry of Education and Science, agreement no. 075-15-2021-691.

Funding

This work was performed within the framework of a state order of the Federal Research Center for Fundamental and Translational Medicine.

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  1. Federal Research Center for Fundamental and Translational Medicine, 630117, Novosibirsk, Russia

    A. V. Chechushkov & E. B. Menshchikova

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  1. A. V. Chechushkov
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  2. E. B. Menshchikova
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Correspondence to E. B. Menshchikova.

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Abbreviations: ROM—reactive oxygen metabolite; TS-13—sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate; ABC—ATP-binding cassette transporter; ARE—antioxidant response element; CLEAR—coordinated lysosomal expression and regulation; LC3B—microtubule-associated proteins 1A/1B light chain 3β; Nrf2—NF-E2-related factor 2; Keap1—Kelch-like ECH-associated protein 1; MDR—multidrug-resistance proteins; MITF—microphthalmia associated transcription fac-tor; p62/SQSTM—ubiquitin-binding protein p62(sequestosome 1); tBHQ—tert-butyl hydroquinone; PBS—phosphate buffered saline; TFE3—transcription factor binding to immunoglobulin heavy constant μ enhancer 3; TFEB—transcription factor EB; TFEC—transcription factor EC.

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Chechushkov, A.V., Menshchikova, E.B. An Investigation of the Regulatory Relationship of the Keap1/Nrf2/ARE Signaling System and Transcriptional Regulators of Lysosomal Biogenesis. Cell Tiss. Biol. 17, 653–661 (2023). https://doi.org/10.1134/S1990519X23060056

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