Caspase-3/7-mediated Cleavage of ?2-spectrin is Required for Acetaminophen-induced Liver Damage.

ABSTRACT:

Unlabelled

The ubiquitously expressed ?2-spectrin (?2SP, SPTBN1) is the most common non-erythrocytic member of the ?-spectrin gene family. Loss of ?2-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 ?2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that ?2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of ?2-spectrin cleavage robustly attenuated ?2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of ?2-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 ?2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of ?2-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

?2-Spectrin, a TGF-? 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 ?2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-? in liver damage.

SUBMITTER: Baek HJ 

PROVIDER: S-EPMC4737674 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature