A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy.
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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Tetsuro
T
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
Liu
Tong
T
Zhai
Peiyong
P
Chen
Wei
W
Li
Hong
H
Molkentin
Jeffery D
JD
Vatner
Stephen F
SF
Sadoshima
Junichi
J
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D016415:Sequence Alignment; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism
C400502:Dnajb5 protein, mouse; D050956:HSP40 Heat-Shock Proteins; C515559:Txn1 protein, mouse; D013879:Thioredoxins; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D003545:Cysteine