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Int J Biol Sci 2016; 12(2):172-183. doi:10.7150/ijbs.13420

Research Paper

Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage

Hye Jung Baek1, Yong Min Lee1, Tae Hyun Kim1, Joo-Young Kim1, Eun Jung Park2, Kuniyoshi Iwabuchi3, Lopa Mishra4, Sang Soo Kim1✉

1. Radiation Medicine Branch, and
2. Cancer Immunology Branch, National Cancer Center, Goyang, Gyeonggi, 410-769, Korea,
3. Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Kahoku-gun, Ishikawa, 920-0293, Japan.
4. Department of Gastroenterology, Hepatology, and Nutrition, MD Anderson Cancer Center, Houston, Texas, 77030, USA

Abstract

The ubiquitously expressed β2-spectrin (β2SP, SPTBN1) is the most common non-erythrocytic member of the β-spectrin gene family. Loss of β2-spectrin leads to defects in liver development, and its haploinsufficiency spontaneously leads to chronic liver disease and the eventual development of hepatocellular cancer. However, the specific role of β2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that β2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of β2-spectrin cleavage robustly attenuated β2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of β2-spectrin were physiologically active, and the N- and C-terminal fragments retained discrete interaction partners and activity in transcriptional regulation and apoptosis, respectively. Cleavage of β2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of β2-spectrin led to resistance to acetaminophen-induced cytotoxicity, and its insufficiency in the liver promoted suppression of acetaminophen-induced liver damage and enhancement of liver regeneration. Conclusions: β2-Spectrin, a TGF-β mediator and signaling molecule, is cleaved and activated by caspase-3/7, consequently enhancing apoptosis and transcriptional control to determine cell fate upon liver damage. These findings have extended our knowledge on the spectrum of β2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-β in liver damage.

Keywords: β2-spectrin, acetaminophen, TGF-β, caspase-3/7, liver damage

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How to cite this article:
Baek HJ, Lee YM, Kim TH, Kim JY, Park EJ, Iwabuchi K, Mishra L, Kim SS. Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage. Int J Biol Sci 2016; 12(2):172-183. doi:10.7150/ijbs.13420. Available from http://www.ijbs.com/v12p0172.htm