The calpain-caspase 12-caspase 3 cascade leading to apoptosis is altered in F508del-CFTR expressing cells

Abstract

In cystic fibrosis (CF), the most frequent mutant variant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del-CFTR protein, is misfolded and retained in the endoplasmic reticulum (ER). We previously showed that the unfolded protein response (UPR) may be triggered in CF. Since prolonged UPR activation leads to apoptosis via the calciumcalpain-caspase-12-caspase-3 cascade and because apoptosis is altered in CF, our aim was to compare the ER stress-induced apoptosis pathway between wild type (Wt) and F508del-CFTR expressing cells. Here we show that the calcium-calpaincaspase-12-caspase-3 cascade is altered in F508del-CFTR expressing cells. We propose that this alteration is involved in the altered apoptosis triggering observed in CF.

Cleavage of caspase‐12 at Asp94, mediated by endoplasmic reticulum stress (ERS), contributes to stretch‐induced apoptosis of myoblasts

“…Caspase‐12 is regarded as a representative molecule implicated in the cell‐death‐executing mechanisms caused by ERS, and caspase‐3 was reported as a substrate of caspase‐12 (Dahmer, ; Hitomi et al, ; Kerbiriou, Teng, Benz, Trouvé, & Férec, ). One of our early studies confirmed the involvement of caspase‐12 in stress‐overloading‐induced apoptosis of myoblasts (Q. Zhang et al, ).…”

Elevated fecal M2‐pyruvate kinase in children with cystic fibrosis: A clue to the increased risk of intestinal malignancy in adulthood?

“…The absence of CFTR may promote changes favorable to neoplasia through perturbations in anti‐apoptotic pathways. Various mechanisms have been described to promote alterations in apoptosis in CF‐affected cells, such as elevated intracellular pH, upregulation of protein kinase CK2 (formerly casein kinase II) expression, and decreased activity of the caspase‐12‐caspase‐3 cascade . Other CFTR‐related mechanisms for the development of gastrointestinal malignancy in CF have also been postulated.…”

“…The underlying pathophysiology for increased cell turnover is unclear, but there is evidence of disruptions in anti‐apoptotic pathways, which favors neoplastic change, as a consequence of absent CFTR . Chronic inflammation within the gastrointestinal tract in CF may also be another potential cause for increased cell turnover . Various studies in inflammatory bowel disease (IBD) have clearly demonstrated the important role of inflammation in the development of small and large intestinal cancers, with greater risk associated with longer duration and greater severity of inflammation .…”

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…Once activated, calpain substrates in the cytosol, nucleus and membrane are hydrolysed resulting in apoptosis [58]. Whereas it was shown that calpains activate the initiator (caspase 12), which subsequently activate downstream effector caspase, caspase 3 [59,60]. Amoebapore and cysteine proteases may serve to directly activate caspase 3.…”