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  3. MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes

MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes

  • Redox Biol. 2024 Mar 28:72:103131. doi: 10.1016/j.redox.2024.103131.
Lorenzo Franci 1,  Giulia Vallini 2,  Franca Maria Bertolino 3,  Vittoria Cicaloni 4,  Giovanni Inzalaco 5,  Mattia Cicogni 6,  Laura Tinti 7,  Laura Calabrese 8,  Virginia Barone 9,  Laura Salvini 10,  Pietro Rubegni 11,  Federico Galvagni 12,  Mario Chiariello 13
Affiliations

Affiliations

  • 1 Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale Delle Ricerche (CNR), Siena, Italy; Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Siena, Italy. Electronic address: lorenzofranci4@gmail.com.
  • 2 Department of Medical Biotechnologies, University of Siena, Siena, Italy; Section of Dermatology, Department of Medical, Surgical and Neurological Science, University of Siena, Italy. Electronic address: giuliavallini19@gmail.com.
  • 3 Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale Delle Ricerche (CNR), Siena, Italy; Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Siena, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy. Electronic address: francamariabertolino@gmail.com.
  • 4 Toscana Life Sciences Foundation, Siena, Italy. Electronic address: v.cicaloni@toscanalifesciences.org.
  • 5 Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale Delle Ricerche (CNR), Siena, Italy; Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Siena, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy. Electronic address: giov.inzalaco@gmail.com.
  • 6 Toscana Life Sciences Foundation, Siena, Italy. Electronic address: m.cicogni@toscanalifesciences.org.
  • 7 Toscana Life Sciences Foundation, Siena, Italy. Electronic address: l.tinti@toscanalifesciences.org.
  • 8 Section of Dermatology, Department of Medical, Surgical and Neurological Science, University of Siena, Italy. Electronic address: laura.calabrese@unisi.it.
  • 9 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. Electronic address: virginia.barone@unisi.it.
  • 10 Toscana Life Sciences Foundation, Siena, Italy. Electronic address: l.salvini@toscanalifesciences.org.
  • 11 Section of Dermatology, Department of Medical, Surgical and Neurological Science, University of Siena, Italy. Electronic address: rubegni@unisi.it.
  • 12 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy. Electronic address: federico.galvagni@unisi.it.
  • 13 Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale Delle Ricerche (CNR), Siena, Italy; Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Siena, Italy. Electronic address: mario.chiariello@cnr.it.
PMID: 38555711 DOI: 10.1016/j.redox.2024.103131
Abstract

Oxidation processes in mitochondria and different environmental insults contribute to unwarranted accumulation of Reactive Oxygen Species (ROS). These, in turn, rapidly damage intracellular lipids, proteins, and DNA, ultimately causing aging and several human diseases. Cells have developed different and very effective systems to control ROS levels. Among these, removal of excessive amounts is guaranteed by upregulated expression of various antioxidant enzymes, through activation of the NF-E2-Related Factor 2 (NRF2) protein. Here, we show that Mitogen Activated Protein Kinase 15 (MAPK15) controls the transactivating potential of NRF2 and, in turn, the expression of its downstream target genes. Specifically, upon oxidative stress, MAPK15 is necessary to increase NRF2 expression and nuclear translocation, by inducing its activating phosphorylation, ultimately supporting transactivation of cytoprotective antioxidant genes. Lungs are continuously exposed to oxidative damages induced by environmental insults such as air pollutants and cigarette smoke. Interestingly, we demonstrate that MAPK15 is very effective in supporting NRF2-dependent antioxidant transcriptional response to cigarette smoke of epithelial lung cells. Oxidative damage induced by cigarette smoke indeed represents a leading cause of disability and death worldwide by contributing to the pathogenesis of different chronic respiratory diseases and lung Cancer. Therefore, the development of novel therapeutic strategies able to modulate cellular responses to oxidative stress would be highly beneficial. Our data contribute to the necessary understanding of the molecular mechanisms behind such responses and identify new potentially actionable targets.

Keywords

Cell signaling; Chronic respiratory diseases; Cigarette smoke; Gene expression; Lung cancer; MAP kinases.

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