A persulfidation-based mechanism controls aquaporin-8 conductance

Stefano Bestetti; Iria Medraño-Fernandez; Mauro Galli; Michela Ghitti; Gerd P. Bienert; Giovanna Musco; Andrea Orsi; Anna Rubartelli; Roberto Sitia

doi:10.1126/sciadv.aar5770

A persulfidation-based mechanism controls aquaporin-8 conductance

Stefano Bestetti, Iria Medraño-Fernandez, Mauro Galli, Michela Ghitti, Gerd P. Bienert, Giovanna Musco, Andrea Orsi, Anna Rubartelli, Roberto Sitia

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H₂O₂ in the extracellular space.We reported previously that aquaporin-8 (AQP8) transports H₂O₂ across the plasma membrane and is reversibly gated during cell stress,modulating signal strength and duration.We showthatAQP8 gating ismediated by persulfidation of cysteine 53 (C53). Treatmentwith H₂S is sufficient to block H₂O₂ entry in unstressed cells. Silencing cystathionine b-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H₂S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H₂O₂ molecules transported through AQP8 sulfenylate C53, making it susceptible to H₂S produced by CBS. This mechanism tunes H₂O₂ transport and may control signaling and limit oxidative stress.

Original language	English
Article number	eaar5770
Journal	Science Advances
Volume	4
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.aar5770
State	Published - 2 May 2018
Externally published	Yes

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title = "A persulfidation-based mechanism controls aquaporin-8 conductance",

abstract = "Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H2O2 in the extracellular space.We reported previously that aquaporin-8 (AQP8) transports H2O2 across the plasma membrane and is reversibly gated during cell stress,modulating signal strength and duration.We showthatAQP8 gating ismediated by persulfidation of cysteine 53 (C53). Treatmentwith H2S is sufficient to block H2O2 entry in unstressed cells. Silencing cystathionine b-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H2S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H2O2 molecules transported through AQP8 sulfenylate C53, making it susceptible to H2S produced by CBS. This mechanism tunes H2O2 transport and may control signaling and limit oxidative stress.",

author = "Stefano Bestetti and Iria Medra{\~n}o-Fernandez and Mauro Galli and Michela Ghitti and Bienert, {Gerd P.} and Giovanna Musco and Andrea Orsi and Anna Rubartelli and Roberto Sitia",

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T1 - A persulfidation-based mechanism controls aquaporin-8 conductance

AU - Bestetti, Stefano

AU - Medraño-Fernandez, Iria

AU - Galli, Mauro

AU - Ghitti, Michela

AU - Bienert, Gerd P.

AU - Musco, Giovanna

AU - Orsi, Andrea

AU - Rubartelli, Anna

AU - Sitia, Roberto

PY - 2018/5/2

Y1 - 2018/5/2

N2 - Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H2O2 in the extracellular space.We reported previously that aquaporin-8 (AQP8) transports H2O2 across the plasma membrane and is reversibly gated during cell stress,modulating signal strength and duration.We showthatAQP8 gating ismediated by persulfidation of cysteine 53 (C53). Treatmentwith H2S is sufficient to block H2O2 entry in unstressed cells. Silencing cystathionine b-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H2S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H2O2 molecules transported through AQP8 sulfenylate C53, making it susceptible to H2S produced by CBS. This mechanism tunes H2O2 transport and may control signaling and limit oxidative stress.

AB - Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H2O2 in the extracellular space.We reported previously that aquaporin-8 (AQP8) transports H2O2 across the plasma membrane and is reversibly gated during cell stress,modulating signal strength and duration.We showthatAQP8 gating ismediated by persulfidation of cysteine 53 (C53). Treatmentwith H2S is sufficient to block H2O2 entry in unstressed cells. Silencing cystathionine b-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H2S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H2O2 molecules transported through AQP8 sulfenylate C53, making it susceptible to H2S produced by CBS. This mechanism tunes H2O2 transport and may control signaling and limit oxidative stress.

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VL - 4

JO - Science Advances

JF - Science Advances

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A persulfidation-based mechanism controls aquaporin-8 conductance

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