A role for annexin A2 in scaffolding the peroxiredoxin 2–STAT3 redox relay complex

Abstract Hydrogen peroxide (H2O2) is recognized to act as a signaling molecule. Peroxiredoxins (Prxs) have the ability to transfer H2O2-derived oxidizing equivalents to redox-regulated target proteins, thus facilitating the transmission of H2O2 signals. It has remained unclear how Prxs and their target proteins are brought together to allow for target-specific protein thiol oxidation. Addressing the specific case of Prx2-dependent STAT3 oxidation, we here show that the association of the two proteins occurs prior to Prx oxidation and depends on a scaffolding protein, the membrane chaperone annexin A2. Deletion or depletion of annexin A2 interrupts the transfer of oxidizing equivalents from Prx2 to STAT3, which is observed to take place on membranes. These findings support the notion that the Prx2-STAT3 redox relay is part of a highly organized membrane signaling domain.

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Prdx1 Interacts with ASK1 upon Exposure to H2O2 and Independently of a Scaffolding Protein

Antioxidants ◽

10.3390/antiox10071060 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1060

Author(s):

Trung Nghia Vo ◽

Julia Malo Pueyo ◽

Khadija Wahni ◽

Daria Ezeriņa ◽

Jesalyn Bolduc ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Protein Interaction ◽

Specific Protein ◽

Annexin A2 ◽

Redox Signaling ◽

Scaffolding Protein ◽

Protein Protein Interaction ◽

Protein Thiols ◽

Vitro Protein

Hydrogen peroxide (H2O2) is a key redox signaling molecule that selectively oxidizes cysteines on proteins. It can accomplish this even in the presence of highly efficient and abundant H2O2 scavengers, peroxiredoxins (Prdxs), as it is the Prdxs themselves that transfer oxidative equivalents to specific protein thiols on target proteins via their redox-relay functionality. The first evidence of a mammalian cytosolic Prdx-mediated redox-relay—Prdx1 with the kinase ASK1—was presented a decade ago based on the outcome of a co-immunoprecipitation experiment. A second such redox-relay—Prdx2:STAT3—soon followed, for which further studies provided insights into its specificity, organization, and mechanism. The Prdx1:ASK1 redox-relay, however, has never undergone such a characterization. Here, we combine cellular and in vitro protein–protein interaction methods to investigate the Prdx1:ASK1 interaction more thoroughly. We show that, contrary to the Prdx2:STAT3 redox-relay, Prdx1 interacts with ASK1 at elevated H2O2 concentrations, and that this interaction can happen independently of a scaffolding protein. We also provide evidence of a Prdx2:ASK1 interaction, and demonstrate that it requires a facilitator that, however, is not annexin A2. Our results reveal that cytosolic Prdx redox-relays can be organized in different ways and yet again highlight the differentiated roles of Prdx1 and Prdx2.

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Lipid peroxidation, protein thiol oxidation and DNA damage in hydrogen peroxide-induced injury to endothelial cells: role of activation of poly(ADP-ribose)polymerase

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/s0167-4889(97)90007-0 ◽

1991 ◽

Vol 1092 (3) ◽

pp. 319-325 ◽

Cited By ~ 94

Author(s):

James B. Kirkland

Keyword(s):

Hydrogen Peroxide ◽

Lipid Peroxidation ◽

Dna Damage ◽

Endothelial Cells ◽

Thiol Oxidation ◽

Protein Thiol ◽

Protein Thiol Oxidation

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Modifying the resolving cysteine affects the structure and hydrogen peroxide reactivity of peroxiredoxin 2

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100494 ◽

2021 ◽

pp. 100494

Author(s):

Alexander V. Peskin ◽

Flavia C. Meotti ◽

Kelsey M. Kean ◽

Christoph Göbl ◽

Albert Souza Peixoto ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Peroxiredoxin 2

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Peroxiredoxin 2 oxidation reveals hydrogen peroxide generation within erythrocytes during high-dose vitamin C administration

Redox Biology ◽

10.1016/j.redox.2021.101980 ◽

2021 ◽

Vol 43 ◽

pp. 101980

Author(s):

Andree G. Pearson ◽

Juliet M. Pullar ◽

John Cook ◽

Emma S. Spencer ◽

Margreet CM. Vissers ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Vitamin C ◽

High Dose ◽

Peroxiredoxin 2 ◽

Hydrogen Peroxide Generation ◽

High Dose Vitamin

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Site-specific Protein Dynamics in Communication Pathway from Sensor to Signaling Domain of Oxygen Sensor Protein, HemAT-Bs

Journal of Biological Chemistry ◽

10.1074/jbc.m112.357855 ◽

2012 ◽

Vol 287 (24) ◽

pp. 19973-19984 ◽

Cited By ~ 10

Author(s):

Samir F. El-Mashtoly ◽

Minoru Kubo ◽

Yuzong Gu ◽

Hitomi Sawai ◽

Satoru Nakashima ◽

...

Keyword(s):

Protein Dynamics ◽

Oxygen Sensor ◽

Specific Protein ◽

Site Specific ◽

Sensor Protein ◽

Signaling Domain ◽

Communication Pathway

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Distinct characteristics of OxyR2, a new OxyR-type regulator, ensuring expression of Peroxiredoxin 2 detoxifying low levels of hydrogen peroxide inVibrio vulnificus

Molecular Microbiology ◽

10.1111/mmi.12712 ◽

2014 ◽

Vol 93 (5) ◽

pp. 992-1009 ◽

Cited By ~ 19

Author(s):

Suyeon Kim ◽

Ye-Ji Bang ◽

Dukyun Kim ◽

Jong Gyu Lim ◽

Man Hwan Oh ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Peroxiredoxin 2 ◽

Low Levels

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Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function

10.1101/2021.11.01.466782 ◽

2021 ◽

Author(s):

Alexei M. Bygrave ◽

Ayesha Sengupta ◽

Ella P. Jackert ◽

Mehroz Ahmed ◽

Beloved Adenuga ◽

...

Keyword(s):

Inhibitory Interneuron ◽

Nmda Receptor Antagonist ◽

Specific Protein ◽

Network Activity ◽

Scaffolding Protein ◽

Inhibitory Interneurons ◽

Cell Type ◽

Cell Type Specific

Synapses in the brain exhibit cell–type–specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell–type–specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron–specific synapse–enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd–95. Intriguingly, we show that Btbd11 can undergo liquid–liquid phase separation when expressed with Psd–95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin–positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell–type–specific protein that supports glutamatergic synapse function in inhibitory interneurons–with implication for circuit function and animal behavior.

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