A tandem activity-based sensing and labeling strategy enables imaging of transcellular hydrogen peroxide signaling

Hidefumi Iwashita; Erika Castillo; Marco S. Messina; Raymond A. Swanson; Christopher J. Chang

doi:10.1073/pnas.2018513118

Edited by Catherine J. Murphy, University of Illinois at Urbana–Champaign, Urbana, IL, and approved January 7, 2021 (received for review September 2, 2020)

Significance

Hydrogen peroxide is a ubiquitous reactive oxygen species (ROS) with diverse signaling and stress contributions, but its transient and mobile nature makes it challenging to study in living systems. Here we report a tandem activity-based sensing and labeling strategy for capture and permanent recording of localized H₂O₂ fluxes by fluorescence imaging. Application of this technology enables direct visualization of ROS transport in cell-to-cell communication using a microglia–neuron coculture model to monitor cell-specific elevations in H₂O₂ levels. In addition to revealing a fundamental contribution of ROS to transcellular signaling, this work presages further opportunities to combine dual chemical sensing and labeling approaches to probe biology with improved spatial fidelity.

Abstract

Reactive oxygen species (ROS) like hydrogen peroxide (H₂O₂) are transient species that have broad actions in signaling and stress, but spatioanatomical understanding of their biology remains insufficient. Here, we report a tandem activity-based sensing and labeling strategy for H₂O₂ imaging that enables capture and permanent recording of localized H₂O₂ fluxes. Peroxy Green-1 Fluoromethyl (PG1-FM) is a diffusible small-molecule probe that senses H₂O₂ by a boronate oxidation reaction to trigger dual release and covalent labeling of a fluorescent product, thus preserving spatial information on local H₂O₂ changes. This unique reagent enables visualization of transcellular redox signaling in a microglia–neuron coculture cell model, where selective activation of microglia for ROS production increases H₂O₂ in nearby neurons. In addition to identifying ROS-mediated cell-to-cell communication, this work provides a starting point for the design of chemical probes that can achieve high spatial fidelity by combining activity-based sensing and labeling strategies.

Footnotes

↵¹To whom correspondence may be addressed. Email: chrischang{at}berkeley.edu.

Author contributions: H.I., E.C., R.A.S., and C.J.C. designed research; H.I., E.C., and M.S.M. performed research; H.I. contributed new reagents/analytic tools; H.I., E.C., M.S.M., R.A.S., and C.J.C. analyzed data; and H.I. and C.J.C. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2018513118/-/DCSupplemental.

Data Availability

All study data are included in the article and/or SI Appendix.

Published under the PNAS license.

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Proceedings of the National Academy of Sciences: 118 (9)

Table of Contents

Submit

[1] ↵
B. D’Autréaux,
M. B. Toledano
, ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol. 8, 813–824 (2007).
OpenUrl CrossRef PubMed

[2] B. D’Autréaux,

[3] M. B. Toledano

[4] ↵
C. C. Winterbourn
, Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol. 4, 278–286 (2008).
OpenUrl CrossRef PubMed

[5] C. C. Winterbourn

[6] ↵
H. M. Cochemé et al
., Measurement of H₂O₂ within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab. 13, 340–350 (2011).
OpenUrl CrossRef PubMed

[7] H. M. Cochemé et al

[8] ↵
M. Schieber,
N. S. Chandel
, ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453–R462 (2014).
OpenUrl CrossRef PubMed

[9] M. Schieber,

[10] N. S. Chandel

[11] ↵
D. Reichmann,
W. Voth,
U. Jakob
, Maintaining a healthy proteome during oxidative stress. Mol. Cell 69, 203–213 (2018).
OpenUrl CrossRef

[12] D. Reichmann,

[13] W. Voth,

[14] U. Jakob

[15] ↵
H. Sies,
D. P. Jones
, Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 21, 363–383 (2020).
OpenUrl CrossRef

[16] H. Sies,

[17] D. P. Jones

[18] ↵
M. C. Dinauer,
S. H. Orkin,
R. Brown,
A. J. Jesaitis,
C. A. Parkos
, The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327, 717–720 (1987).
OpenUrl CrossRef PubMed

[19] M. C. Dinauer,

[20] S. H. Orkin,

[21] R. Brown,

[22] A. J. Jesaitis,

[23] C. A. Parkos

[24] ↵
B. D. Volpp,
W. M. Nauseef,
R. A. Clark
, Two cytosolic neutrophil oxidase components absent in autosomal chronic granulomatous disease. Science 242, 1295–1297 (1988).
OpenUrl Abstract/FREE Full Text

[25] B. D. Volpp,

[26] W. M. Nauseef,

[27] R. A. Clark

[28] ↵
R. A. Clark et al
., Genetic variants of chronic granulomatous disease: Prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. N. Engl. J. Med. 321, 647–652 (1989).
OpenUrl CrossRef PubMed

[29] R. A. Clark et al

[30] ↵
J. D. Lambeth
, NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189 (2004).
OpenUrl CrossRef PubMed

[31] J. D. Lambeth

[32] ↵
A. Kamsler,
M. Segal
, Hydrogen peroxide modulation of synaptic plasticity. J. Neurosci. 23, 269–276 (2003).
OpenUrl Abstract/FREE Full Text

[33] A. Kamsler,

[34] M. Segal

[35] ↵
M. V. Tejada-Simon et al
., Synaptic localization of a functional NADPH oxidase in the mouse hippocampus. Mol. Cell. Neurosci. 29, 97–106 (2005).
OpenUrl CrossRef PubMed

[36] M. V. Tejada-Simon et al

[37] ↵
A. M. Brennan et al
., NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat. Neurosci. 12, 857–863 (2009).
OpenUrl CrossRef PubMed

[38] A. M. Brennan et al

[39] ↵
R. De Pasquale,
T. F. Beckhauser,
M. S. Hernandes,
L. R. Giorgetti Britto
, LTP and LTD in the visual cortex require the activation of NOX2. J. Neurosci. 34, 12778–12787 (2014).
OpenUrl Abstract/FREE Full Text

[40] R. De Pasquale,

[41] T. F. Beckhauser,

[42] M. S. Hernandes,

[43] L. R. Giorgetti Britto

[44] ↵
B. C. Dickinson,
J. Peltier,
D. Stone,
D. V. Schaffer,
C. J. Chang
, Nox2 redox signaling maintains essential cell populations in the brain. Nat. Chem. Biol. 7, 106–112 (2011).
OpenUrl CrossRef PubMed

[45] B. C. Dickinson,

[46] J. Peltier,

[47] D. Stone,

[48] D. V. Schaffer,

[49] C. J. Chang

[50] ↵
J. E. Le Belle et al
., Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 8, 59–71 (2011).
OpenUrl CrossRef PubMed

[51] J. E. Le Belle et al

[52] ↵
C. Xu,
J. Luo,
L. He,
C. Montell,
N. Perrimon
, Oxidative stress induces stem cell proliferation via TRPA1/RyR-mediated Ca²⁺ signaling in the Drosophila midgut. eLife 6, e22441 (2017).
OpenUrl CrossRef

[53] C. Xu,

[54] J. Luo,

[55] L. He,

[56] C. Montell,

[57] N. Perrimon

[58] ↵
J. S. O’Neill,
A. B. Reddy
, Circadian clocks in human red blood cells. Nature 469, 498–503 (2011).
OpenUrl CrossRef PubMed

[59] J. S. O’Neill,

[60] A. B. Reddy

[61] ↵
R. S. Wible et al
., NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus. eLife 7, e31656 (2018).
OpenUrl

[62] R. S. Wible et al

[63] ↵
J. F. Pei et al
., Diurnal oscillations of endogenous H₂O₂ sustained by p66^Shc regulate circadian clocks. Nat. Cell Biol. 21, 1553–1564 (2019).
OpenUrl

[64] J. F. Pei et al

[65] ↵
P. Niethammer,
C. Grabher,
A. T. Look,
T. J. Mitchison
, A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009).
OpenUrl CrossRef PubMed

[66] P. Niethammer,

[67] C. Grabher,

[68] A. T. Look,

[69] T. J. Mitchison

[70] ↵
A. Hervera et al
., Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons. Nat. Cell Biol. 20, 307–319 (2018).
OpenUrl CrossRef PubMed

[71] A. Hervera et al

[72] ↵
E. W. Miller,
B. C. Dickinson,
C. J. Chang
, Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. Proc. Natl. Acad. Sci. U.S.A. 107, 15681–15686 (2010).
OpenUrl Abstract/FREE Full Text

[73] E. W. Miller,

[74] B. C. Dickinson,

[75] C. J. Chang

[76] ↵
G. P. Bienert et al
., Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes. J. Biol. Chem. 282, 1183–1192 (2007).
OpenUrl Abstract/FREE Full Text

[77] G. P. Bienert et al

[78] ↵
M. Dynowski,
G. Schaaf,
D. Loque,
O. Moran,
U. Ludewig
, Plant plasma membrane water channels conduct the signalling molecule H₂O₂. Biochem. J. 414, 53–61 (2008).
OpenUrl Abstract/FREE Full Text

[79] M. Dynowski,

[80] G. Schaaf,

[81] D. Loque,

[82] O. Moran,

[83] U. Ludewig

[84] ↵
O. Rodrigues et al
., Aquaporins facilitate hydrogen peroxide entry into guard cells to mediate ABA- and pathogen-triggered stomatal closure. Proc. Natl. Acad. Sci. U.S.A. 114, 9200–9205 (2017).
OpenUrl Abstract/FREE Full Text

[85] O. Rodrigues et al

[86] ↵
C. Rodrigues et al
., Human aquaporin-5 facilitates hydrogen peroxide permeation affecting adaption to oxidative stress and cancer cell migration. Cancers (Basel) 11, 932 (2019).
OpenUrl

[87] C. Rodrigues et al

[88] ↵
J. García-Calvo et al
., Fluorescent membrane tension probes for super-resolution microscopy: Combining mechanosensitive cascade switching with dynamic-covalent ketone chemistry. J. Am. Chem. Soc. 142, 12034–12038 (2020).
OpenUrl

[89] J. García-Calvo et al

[90] ↵
N. Panyain et al
., Discovery of a potent and selective covalent inhibitor and activity-based probe for the deubiquitylating enzyme UCHL1, with antifibrotic activity. J. Am. Chem. Soc. 142, 12020–12026 (2020).
OpenUrl

[91] N. Panyain et al

[92] ↵
G. J. Brighty et al
., Using sulfuramidimidoyl fluorides that undergo sulfur(VI) fluoride exchange for inverse drug discovery. Nat. Chem. 12, 906–913 (2020).
OpenUrl

[93] G. J. Brighty et al

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A tandem activity-based sensing and labeling strategy enables imaging of transcellular hydrogen peroxide signaling

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