TY - JOUR
T1 - A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy
AU - Ago, Tetsuro
AU - Liu, Tong
AU - Zhai, Peiyong
AU - Chen, Wei
AU - Li, Hong
AU - Molkentin, Jeffery D.
AU - Vatner, Stephen F.
AU - Sadoshima, Junichi
N1 - Funding Information:
The authors thank Daniela Zablocki for critical reading of the manuscript. This work was supported in part by U.S. Public Health Service Grants HL 59139, HL67727, HL69020, AG23039, AG28787, and HL91469 and by American Heart Association grant 0340123N.
PY - 2008/6/13
Y1 - 2008/6/13
N2 - Thioredoxin 1 (Trx1) facilitates the reduction of signaling molecules and transcription factors by cysteine thiol-disulfide exchange, thereby regulating cell growth and death. Here we studied the molecular mechanism by which Trx1 attenuates cardiac hypertrophy. Trx1 upregulates DnaJb5, a heat shock protein 40, and forms a multiple-protein complex with DnaJb5 and class II histone deacetylases (HDACs), master negative regulators of cardiac hypertrophy. Both Cys-274/Cys-276 in DnaJb5 and Cys-667/Cys-669 in HDAC4 are oxidized and form intramolecular disulfide bonds in response to reactive oxygen species (ROS)-generating hypertrophic stimuli, such as phenylephrine, whereas they are reduced by Trx1. Whereas reduction of Cys-274/Cys-276 in DnaJb5 is essential for interaction between DnaJb5 and HDAC4, reduction of Cys-667/Cys-669 in HDAC4 inhibits its nuclear export, independently of its phosphorylation status. Our study reveals a novel regulatory mechanism of cardiac hypertrophy through which the nucleocytoplasmic shuttling of class II HDACs is modulated by their redox modification in a Trx1-sensitive manner.
AB - Thioredoxin 1 (Trx1) facilitates the reduction of signaling molecules and transcription factors by cysteine thiol-disulfide exchange, thereby regulating cell growth and death. Here we studied the molecular mechanism by which Trx1 attenuates cardiac hypertrophy. Trx1 upregulates DnaJb5, a heat shock protein 40, and forms a multiple-protein complex with DnaJb5 and class II histone deacetylases (HDACs), master negative regulators of cardiac hypertrophy. Both Cys-274/Cys-276 in DnaJb5 and Cys-667/Cys-669 in HDAC4 are oxidized and form intramolecular disulfide bonds in response to reactive oxygen species (ROS)-generating hypertrophic stimuli, such as phenylephrine, whereas they are reduced by Trx1. Whereas reduction of Cys-274/Cys-276 in DnaJb5 is essential for interaction between DnaJb5 and HDAC4, reduction of Cys-667/Cys-669 in HDAC4 inhibits its nuclear export, independently of its phosphorylation status. Our study reveals a novel regulatory mechanism of cardiac hypertrophy through which the nucleocytoplasmic shuttling of class II HDACs is modulated by their redox modification in a Trx1-sensitive manner.
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U2 - 10.1016/j.cell.2008.04.041
DO - 10.1016/j.cell.2008.04.041
M3 - Article
C2 - 18555775
AN - SCOPUS:44649184557
SN - 0092-8674
VL - 133
SP - 978
EP - 993
JO - Cell
JF - Cell
IS - 6
ER -