Mechanisms underlying Nrf2 nuclear translocation by non-lethal levels of hydrogen peroxide: p38 MAPK-dependent neutral sphingomyelinase2 membrane trafficking and ceramide/PKCζ/CK2 signaling: Mechanism of Nrf2 nuclear translocation by H₂O₂

TY - JOUR

T1 - Mechanisms underlying Nrf2 nuclear translocation by non-lethal levels of hydrogen peroxide

T2 - p38 MAPK-dependent neutral sphingomyelinase2 membrane trafficking and ceramide/PKCζ/CK2 signaling: Mechanism of Nrf2 nuclear translocation by H2O2

AU - Ishii, Tetsuro

AU - Warabi, Eiji

AU - Mann, Giovanni E.

N1 - Funding Information: We gratefully acknowledge The Great Britain SASAKAWA Foundation for a Butterfield Award supporting our UK-Japan collaboration between the University of Tsukuba, Japan (T.I. E.W.) and King's College London, UK (G.E.M.). We further acknowledge support from the Japanese Society for Promotion of Science, KAKENHI (E.W. JP19790178), British Heart Foundation (G.E.M.), Heart Research UK (G.E.M.) and COST Action ‘BenBedPhar’ CA20121 (G.E.M.). Funding Information: We gratefully acknowledge The Great Britain SASAKAWA Foundation for a Butterfield Award supporting our UK-Japan collaboration between the University of Tsukuba, Japan (T.I., E.W.) and King's College London, UK (G.E.M.). We further acknowledge support from the Japanese Society for Promotion of Science, KAKENHI (E.W. JP19790178), British Heart Foundation (G.E.M.), Heart Research UK (G.E.M.) and COST Action ‘BenBedPhar’ CA20121 (G.E.M.). Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/10/1

Y1 - 2022/10/1

N2 - Hydrogen peroxide is an aerobic metabolite playing a central role in redox signaling and oxidative stress. H2O2 could activate redox sensitive transcription factors, such as Nrf2, AP-1 and NF-κB by different manners. In some cells, treatment with non-lethal levels of H2O2 induces rapid activation of Nrf2, which upregulates expression of a set of genes involved in glutathione (GSH) synthesis and defenses against oxidative damage. It depends on two steps, the rapid translational activation of Nrf2 and facilitation of Nrf2 nuclear translocation. We review the molecular mechanisms by which H2O2 induces nuclear translocation of Nrf2 in cultured cells by highlighting the role of neutral sphingomyelinase 2 (nSMase2), a GSH sensor. H2O2 enters cells through aquaporin channels in the plasma membrane and is rapidly reduced to H2O by GSH peroxidases to consume cellular GSH, resulting in nSMase2 activation to generate ceramide. H2O2 also activates p38 MAP kinase, which enhances transfer of nSMase2 from perinuclear regions to plasma membrane lipid rafts to accelerate ceramide generation. Low levels of ceramide activate PKCζ, which then activates casein kinase 2 (CK2). These protein kinases are able to phosphorylate Nrf2 to stabilize and activate it. Notably, Nrf2 also binds to caveolin-1 (Cav1), which protects Nrf2 from Keap1-mediated degradation and limits Nrf2 nuclear translocation. We propose that Cav1serves as a signaling hub for the control of H2O2-mediated phosphorylation of Nrf2 by kinases, which results in release of Nrf2 from Cav1 to facilitate nuclear translocation. In summary, H2O2 induces GSH depletion which is recovered by Nrf2 activation dependent on p38/nSMase2/ceramide signaling.

AB - Hydrogen peroxide is an aerobic metabolite playing a central role in redox signaling and oxidative stress. H2O2 could activate redox sensitive transcription factors, such as Nrf2, AP-1 and NF-κB by different manners. In some cells, treatment with non-lethal levels of H2O2 induces rapid activation of Nrf2, which upregulates expression of a set of genes involved in glutathione (GSH) synthesis and defenses against oxidative damage. It depends on two steps, the rapid translational activation of Nrf2 and facilitation of Nrf2 nuclear translocation. We review the molecular mechanisms by which H2O2 induces nuclear translocation of Nrf2 in cultured cells by highlighting the role of neutral sphingomyelinase 2 (nSMase2), a GSH sensor. H2O2 enters cells through aquaporin channels in the plasma membrane and is rapidly reduced to H2O by GSH peroxidases to consume cellular GSH, resulting in nSMase2 activation to generate ceramide. H2O2 also activates p38 MAP kinase, which enhances transfer of nSMase2 from perinuclear regions to plasma membrane lipid rafts to accelerate ceramide generation. Low levels of ceramide activate PKCζ, which then activates casein kinase 2 (CK2). These protein kinases are able to phosphorylate Nrf2 to stabilize and activate it. Notably, Nrf2 also binds to caveolin-1 (Cav1), which protects Nrf2 from Keap1-mediated degradation and limits Nrf2 nuclear translocation. We propose that Cav1serves as a signaling hub for the control of H2O2-mediated phosphorylation of Nrf2 by kinases, which results in release of Nrf2 from Cav1 to facilitate nuclear translocation. In summary, H2O2 induces GSH depletion which is recovered by Nrf2 activation dependent on p38/nSMase2/ceramide signaling.

KW - HO

KW - Neutral sphingomyelinase 2

KW - Nrf2

KW - p38

KW - PKCζ

UR - http://www.scopus.com/inward/record.url?scp=85137331702&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2022.08.036

DO - 10.1016/j.freeradbiomed.2022.08.036

M3 - Review article

C2 - 36064071

AN - SCOPUS:85137331702

SN - 0891-5849

VL - 191

SP - 191

EP - 202

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -