Abstract
Reactive oxygen species (ROS) are not only toxic substances inducing oxidative stress but also play a role in receptor signaling as a second messenger, which augments signaling through various receptors by oxidizing ROS-sensitive signaling molecules. Among ROS, H2O2 is suggested to be an important second messenger because of its relative stability. H2O2 is generated by superoxide dismutase (SOD)-mediated conversion of superoxide produced by membrane-localized NADPH oxidases (NOXes). Superoxide and H2O2 are also produced as a by-product of mitochondrial respiratory chain and various other metabolic reactions. BCR ligation induces ROS production in two phases. ROS production starts immediately after BCR ligation and ceases in 1 h, then re-starts 2 h after BCR ligation and lasts 4–6 h. ROS production in the early phase is mediated by NOX2, a NOX isoform, but does not regulate BCR signaling. In contrast, ROS production at the late phase augments BCR signaling. Although the involvement of mitochondrial respiration was previously suggested in prolonged BCR ligation-induced ROS production, we recently demonstrated that NOX3, another NOX isoform, plays a central role in ROS production at the late phase. NOXes are shown to be a component of ROS-generating signaling endosome called redoxosome together with endocytosed receptors and receptor-associated signaling molecules. In redoxosome, ROS generated by NOXes augment signaling through the endocytosed receptor. The role of NOXes and redoxosome in BCR signaling needs to be further elucidated.
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Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB, Rhee SG (1997) Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272:217–221
Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313
Brandes RP, Weissmann N, Schroder K (2014) Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med 76:208–226
Capasso M, Bhamrah MK, Henley T, Boyd RS, Langlais C, Cain K, Dinsdale D, Pulford K, Khan M, Musset B et al (2010) HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species. Nat Immunol 11:265–272
Capasso M, DeCoursey TE, Dyer MJ (2011) pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. Trends Cell Biol 21:20–28
Chaturvedi A, Martz R, Dorward D, Waisberg M, Pierce SK (2011) Endocytosed BCRs sequentially regulate MAPK and Akt signaling pathways from intracellular compartments. Nat Immunol 12:1119–1126
Corcoran A, Cotter TG (2013) Redox regulation of protein kinases. FEBS J 280:1944–1965
Di Marzo N, Chisci E, Giovannoni R (2018) The role of hydrogen peroxide in redox-dependent signaling: homeostatic and pathological responses in mammalian cells. Cells 7:156
Feng YY, Tang M, Suzuki M, Gunasekara C, Anbe Y, Hiraoka Y, Liu J, Grasberger H, Ohkita M, Matsumura Y et al (2019) Essential role of NADPH oxidase-dependent production of reactive oxygen species in maintenance of sustained B cell receptor signaling and B cell proliferation. J Immunol 202:2546–2557
Gimenez M, Schickling BM, Lopes LR, Miller FJ Jr (2016) Nox1 in cardiovascular diseases: regulation and pathophysiology. Clin Sci (Lond) 130:151–165
Hempel N, Trebak M (2017) Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium 63:70–96
Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15:411–421
Lee SR, Kwon KS, Kim SR, Rhee SG (1998) Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 273:15366–15372
Li Q, Harraz MM, Zhou W, Zhang LN, Ding W, Zhang Y, Eggleston T, Yeaman C, Banfi B, Engelhardt JF (2006) Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes. Mol Cell Biol 26:140–154
Li Q, Spencer NY, Oakley FD, Buettner GR, Engelhardt JF (2009) Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. Antioxid Redox Signal 11:1249–1263
Lismont C, Revenco I, Fransen M (2019) Peroxisomal hydrogen peroxide metabolism and signaling in health and disease. Int J Mol Sci 20:3673
Lustgarten MS, Bhattacharya A, Muller FL, Jang YC, Shimizu T, Shirasawa T, Richardson A, Van Remmen H (2012) Complex I generated, mitochondrial matrix-directed superoxide is released from the mitochondria through voltage dependent anion channels. Biochem Biophys Res Commun 422:515–521
Marinho HS, Real C, Cyrne L, Soares H, Antunes F (2014) Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox Biol 2:535–562
Meng TC, Fukada T, Tonks NK (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9:387–399
Miller FJ Jr, Filali M, Huss GJ, Stanic B, Chamseddine A, Barna TJ, Lamb FS (2007) Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC-3. Circ Res 101:663–671
Murphy JE, Padilla BE, Hasdemir B, Cottrell GS, Bunnett NW (2009) Endosomes: a legitimate platform for the signaling train. Proc Natl Acad Sci USA 106:17615–17622
Oakley FD, Smith RL, Engelhardt JF (2009) Lipid rafts and caveolin-1 coordinate interleukin-1beta (IL-1beta)-dependent activation of NFkappaB by controlling endocytosis of Nox2 and IL-1beta receptor 1 from the plasma membrane. J Biol Chem 284:33255–33264
Prieto-Bermejo R, Hernandez-Hernandez A (2017) The importance of NADPH oxidases and redox signaling in angiogenesis. Antioxidants (Basel) 6:32
Quijano C, Trujillo M, Castro L, Trostchansky A (2016) Interplay between oxidant species and energy metabolism. Redox Biol 8:28–42
Reczek CR, Chandel NS (2015) ROS-dependent signal transduction. Curr Opin Cell Biol 33:8–13
Richards SM, Clark EA (2009) BCR-induced superoxide negatively regulates B-cell proliferation and T-cell-independent type 2 Ab responses. Eur J Immunol 39:3395–3403
Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24:R453–R462
Singh DK, Kumar D, Siddiqui Z, Basu SK, Kumar V, Rao KV (2005) The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121:281–293
Spencer NY, Engelhardt JF (2014) The basic biology of redoxosomes in cytokine-mediated signal transduction and implications for disease-specific therapies. Biochemistry 53:1551–1564
Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299
Tsutsumi R, Harizanova J, Stockert R, Schroder K, Bastiaens PIH, Neel BG (2017) Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2. Nat Commun 8:466
Wheeler ML, Defranco AL (2012) Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J Immunol 189:4405–4416
Wienands J, Larbolette O, Reth M (1996) Evidence for a preformed transducer complex organized by the B cell antigen receptor. Proc Natl Acad Sci USA 93:7865–7870
Yoboue ED, Sitia R, Simmen T (2018) Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages. Cell Death Dis 9:331
Zito E (2015) ERO1: A protein disulfide oxidase and H2O2 producer. Free Radic Biol Med 83:299–304
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Tsubata, T. (2020). Involvement of Reactive Oxygen Species (ROS) in BCR Signaling as a Second Messenger. In: Wang, JY. (eds) B Cells in Immunity and Tolerance. Advances in Experimental Medicine and Biology, vol 1254. Springer, Singapore. https://doi.org/10.1007/978-981-15-3532-1_3
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DOI: https://doi.org/10.1007/978-981-15-3532-1_3
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