Cross-Talk between Two Cysteine Protease Families

TLDR

Calpains and caspases are two cysteine protease families that play important roles in regulating pathological cell death. We propose that disturbance to intracellular calcium storage caused by ischemic injury or amyloid β peptide cytotoxicity induces apoptosis through calpain‑mediated activation of caspase‑12 and inactivation of Bcl‑xL. Disturbance of intracellular calcium storage from ischemic injury or amyloid β peptide cytotoxicity activates calpain, which then cleaves procaspase‑12 and Bcl‑xL, triggering apoptosis. Our data show that m‑calpain cleaves procaspase‑12 to activate caspase‑12 and cleaves Bcl‑xL’s loop region, converting it to a pro‑apoptotic form, thereby revealing a calcium‑mediated calpain–caspase cross‑talk apoptotic pathway.

Abstract

Calpains and caspases are two cysteine protease families that play important roles in regulating pathological cell death. Here, we report that m-calpain may be responsible for cleaving procaspase-12, a caspase localized in the ER, to generate active caspase-12. In addition, calpain may be responsible for cleaving the loop region in Bcl-xL and, therefore, turning an antiapoptotic molecule into a proapoptotic molecule. We propose that disturbance to intracellular calcium storage as a result of ischemic injury or amyloid β peptide cytotoxicity may induce apoptosis through calpain- mediated caspase-12 activation and Bcl-xL inactivation. These data suggest a novel apoptotic pathway involving calcium-mediated calpain activation and cross-talks between calpain and caspase families.