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

Baek, Hye Jung; Lee, Yong Min; Kim, Tae Hyun; Kim, Joo-Young; Park, Eun Jung; Iwabuchi, Kuniyoshi; Mishra, Lopa; Kim, Sang Soo

doi:10.7150/ijbs.13420

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

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 Kim^1✉

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

Citation:

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. https://www.ijbs.com/v12p0172.htm

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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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APA

Baek, H.J., Lee, Y.M., Kim, T.H., Kim, J.Y., Park, E.J., Iwabuchi, K., Mishra, L., Kim, S.S. (2016). Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage. International Journal of Biological Sciences, 12(2), 172-183. https://doi.org/10.7150/ijbs.13420.

ACS

Baek, H.J.; Lee, Y.M.; Kim, T.H.; Kim, J.Y.; Park, E.J.; Iwabuchi, K.; Mishra, L.; Kim, S.S. 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.

NLM

CSE

Baek HJ, Lee YM, Kim TH, Kim JY, Park EJ, Iwabuchi K, Mishra L, Kim SS. 2016. Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage. Int J Biol Sci. 12(2):172-183.

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