Differential functions of calpain 1 during epithelial cell death and adipocyte differentiation in mammary gland involution

Abstract

Calpains become activated in the mammary gland early during weaning, cleaving several proteins located mainly in the cell membrane, but also in other organelles such as lysosomes, mitochondria and nuclei. By immunofluorescence and Western blot analysis, we have demonstrated the nuclear translocation of calpain-1 and calpain-2, together with the cleavage of several cytoplasmic nucleoporins in epithelial cells of the lobulo-alveolar compartment. In vivo and in vitro calpain inhibition prevented this nucleoporin degradation. In addition, calpain-1 was also present in the nucleus of non-epithelial mammary tissue cells, concomitant with adipocyte re-differentiation. Calpain-1 was internalized within nuclei and found to be present in the nuclear chromatin-enriched fraction, associated with histone H3. Furthermore, we have demonstrated, both in vivo and in vitro, the cleavage of the N-terminal residue of histone H3 by calpain-1. Calpain-1 co-localized with both H3K4me3 (histone H3 trimethylated at Lys4) and H3K27me3 (histone H3 trimethylated at Lys27) at the nuclear periphery, a bivalent epigenetic signal essential for cell differentiation. Using ChIP assays we could confirm the presence of calpain-1 in the promoters of key genes expressed in adipose tissue, such as Cebpa (CCAAT/enhancer-binding protein α) and Lep (leptin). The results of the present study highlight a dual role for calpain-1 in the weaned gland after the pregnancy/lactation cycle, controlling programmed cell death and participating in the epigenetic programme during adipocyte differentiation.

Fibrosis resolution in the mouse liver: role of Mmp12 and potential role of Calpain 1/2

“…Moreover, calpain activation has been identified to be involved in diseases of remodeling (i.e., fibrosis) via mechanisms that remain unclear (54). Interestingly, the predicted substrates for calpain activation not only included key ECM proteins [e.g., collagens and fibrin(ogens)], but also nuclear proteins, such as histones (Figure 6C), which is in-line with previous findings (55). Few studies have identified calpain activation to play a role in hepatic injury.…”

Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

“…Malfunction of nucleo-cytoplasmic transport caused by Ca 2+ dysregulation has been proposed to occur in degenerative diseases39, and excess Ca 2+ influx reportedly disrupts nucleo-cytoplasmic transport as a result of calpain-dependent degradation of NPC components104041, including nuclear lamins and Nups. Disruption of the NPC enabled redistribution of calpains from the cytoplasm to the nucleus across the nuclear membrane during an acute excitotoxic insult10, but the pathogenic role of NPC disruption and the occurrence of NPC disruption during the slow neuronal death process have not been demonstrated.…”

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

“…Although we do not yet know the molecular steps that link calpainopathy to eosinophilic responses, it is notable that CAPN14 belongs to the classical calpain sub-family that comprises one of the major proteolytic systems that mediate protein cleavage (in addition to the proteasome, lysosome, and caspase systems) 47 . Classical calpains are calcium regulatory proteases and their substrates include structural proteins, signaling molecules, transcription factors 48 , 49 , and inflammatory mediators that are germane for allergic responses, such as STAT-6 (signal transducer and activator of transcription 6) and IL-33 50 , 51 , the latter of which shows some linkage with EoE ( Supplementary Figure 7 , Table 2 ). On the basis of the collective data, we propose a model that links the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14 .…”