Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1

Ji Soo Chae; Sang Gil Hwang; Dae Sik Lim; Eui Ju Choi

doi:10.1016/j.freeradbiomed.2012.10.527

Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1

Ji Soo Chae
, Sang Gil Hwang
, Dae Sik Lim
, Eui Ju Choi^*

^*Corresponding author for this work

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

39 Citations (Scopus)

Abstract

The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H₂O₂. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-α prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-α on MST1 activation was reversed by the reducing agent N-acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1.

Original language	English
Pages (from-to)	2335-2343
Number of pages	9
Journal	Free Radical Biology and Medicine
Volume	53
Issue number	12
DOIs	https://doi.org/10.1016/j.freeradbiomed.2012.10.527
Publication status	Published - 2012 Dec 15

Bibliographical note

Funding Information:
This work was supported by a grant from the Seoul R&BD Program ( ST100079 ) and by an NRF grant ( 2006–0093855, 2011–0030141 ) funded by the Ministry of Education, Science & Technology of the Korea (E.-J.C.) .

Keywords

Free radicals
MST1
Reactive oxygen species
TNF-α
Thioredoxin-1

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2012.10.527

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title = "Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1",

abstract = "The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H2O2. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-α prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-α on MST1 activation was reversed by the reducing agent N-acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1.",

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author = "Chae, \{Ji Soo\} and \{Gil Hwang\}, Sang and Lim, \{Dae Sik\} and Choi, \{Eui Ju\}",

note = "Funding Information: This work was supported by a grant from the Seoul R\&BD Program ( ST100079 ) and by an NRF grant ( 2006–0093855, 2011–0030141 ) funded by the Ministry of Education, Science \& Technology of the Korea (E.-J.C.) . ",

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AU - Lim, Dae Sik

AU - Choi, Eui Ju

N1 - Funding Information: This work was supported by a grant from the Seoul R&BD Program ( ST100079 ) and by an NRF grant ( 2006–0093855, 2011–0030141 ) funded by the Ministry of Education, Science & Technology of the Korea (E.-J.C.) .

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N2 - The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H2O2. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-α prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-α on MST1 activation was reversed by the reducing agent N-acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1.

AB - The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H2O2. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-α prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-α on MST1 activation was reversed by the reducing agent N-acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1.

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KW - Reactive oxygen species

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Thioredoxin-1 functions as a molecular switch regulating the oxidative stress-induced activation of MST1

Abstract

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Keywords

ASJC Scopus subject areas

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