Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases.
In three-dimensional extracellular matrix, mesenchymal cells including hepatic stellate cells (HSCs) gain the ability to express matrix metalloproteinases (MMPs) on injury signals. In contrast, in myofibroblastic HSCs in fibrotic liver, many MMP genes are silenced into an epigenetically nonpermissive state. The mechanism by which the three-dimensional extracellular matrix confers the MMP genes into an epigenetically permissive state has not been well characterized. In continuation of previous work, we show here that the up-regulation of MMP genes is mediated through degradation of class IIa histone deacetylases (HDACs) by certain cysteine cathepsins (Cts). In three-dimensional extracellular matrix culture, CtsH, among other cysteine cathepsins, was up-regulated and localized as puncta in the nuclear and cytoplasmic compartments in a complex with HDAC4 for its degradation. Conversely, along with HSC trans-differentiation, CtsH and CtsL were progressively down-regulated, whereas HDAC4 was concurrently stabilized. The inhibition of cysteine cathepsins by specific proteinase inhibitors or chloroquine, which raises cellular pH, restored HDAC4. Recombinant CtsH could break down HDAC4 in the transfected cells and in vitro at acidic pH. In human cirrhotic liver, activated HSCs express high levels of class IIa HDACs but little CtsH. We propose that cysteine cathepsin-mediated degradation of class IIa HDACs plays a key role in the modulation of MMP expression/suppression and HSC functions in tissue injury and fibrosis.
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Zemin
Z
Yang
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Yu
Y
Liu
Department of Surgery, University of Southern California, Los Angeles, California.
Lan
L
Qin
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Pengfei
P
Wu
State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, China.
Zanxian
Z
Xia
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China; Chengdu Public Health Clinical Center, Chengdu, China.
Mei
M
Luo
Chengdu Public Health Clinical Center, Chengdu, China.
Yilan
Y
Zeng
Department of Surgery, University of Southern California, Los Angeles, California.
Hidekazu
H
Tsukamoto
Chengdu Tongde Pharmaceutical Co. Ltd., Chengdu, China.
Zongyun
Z
Ju
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Danmei
D
Su
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Han
H
Kang
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China.
Zhixiong
Z
Xiao
Beijing YouAn Hospital, Capital Medical University, Beijing, China.
Sujun
S
Zheng
Beijing YouAn Hospital, Capital Medical University, Beijing, China.
Zhongping
Z
Duan
Olive View-UCLA Medical Center, Los Angeles, California.
Richard
R
Hu
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Qiang
Q
Wang
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Stephen J
SJ
Pandol
The Center for Growth, Metabolism and Aging, and the Key Laboratory for Bio-Resource and Eco-Environment of Education of Ministry, College of Life Sciences, Sichuan University, Chengdu, China; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: hanyp@scu.edu.cn.
Yuan-Ping
YP
Han
D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D056655:Cathepsin H / Q000378:metabolism*; D056668:Cathepsin L / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D054338:Cell Transdifferentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004795:Enzyme Stability / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D056668:Cathepsin L; D056655:Cathepsin H; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9; C400300:HDAC4 protein, human; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases