title: Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage.
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.
authors.affiliation: 1. Radiation Medicine Branch, and.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Baek
authors.affiliation: 1. Radiation Medicine Branch, and.
authors.forename: Yong Min
authors.initials: YM
authors.lastname: Lee
authors.affiliation: 1. Radiation Medicine Branch, and.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: 1. Radiation Medicine Branch, and.
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: 2. Cancer Immunology Branch, National Cancer Center, Goyang, Gyeonggi, 410-769, Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: 3. Department of Biochemistry I, School of Medicine, Kanazawa Medical University, Kahoku-gun, Ishikawa, 920-0293, Japan.
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Iwabuchi
authors.affiliation: 4. Department of Gastroenterology, Hepatology, and Nutrition, MD Anderson Cancer Center, Houston, Texas, 77030, USA.
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
authors.affiliation: 1. Radiation Medicine Branch, and.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kim
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism / Q000502:physiology*; D053179:Caspase 7 / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013049:Spectrin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; C452439:SPTBN1 protein, human; D016212:Transforming Growth Factor beta; D013049:Spectrin; D000082:Acetaminophen; D053148:Caspase 3; D053179:Caspase 7
keywords: TGF-β; acetaminophen; caspase-3/7; liver damage; β2-spectrin