Calpains

Calpains are a class of intracellular, calcium-dependent cysteine (Cys) proteases. Under physiological conditions, calpain activation is regulated by transient and localized calcium fluxes from extracellular or intracellular calcium stores. In humans, there are 16 calpain proteases that are categorized into different groups based on their expression profile or domain structure (Ono Y et al. 2012).

Among them, calpain-14 (CAPN14) is a comparatively new classical representative of calpains, which was relatively unexplored until our recent discovery that it is etiologically associated with eosinophilic esophagitis (EoE) (Kottyan LC et al. 2014; Sleiman PMA et al. 2014).

Calpain dysregulation has been identified in patients with a number of genetic and acquired diseases. In particular, idiopathic eosinophilic myositis (Krahn M et al. 2007; Selva-O'Callaghan A et al. 2014) is a known pathophysiological component of calpain dysregulation. Mechanistically, it is possible that CAPN3 acts as a sensor for the integrity and function of the sarcomere and is involved in its repair and maintenance. Deficiency of CAPN3 also increases oxidative stress in the mitochondria due to the accumulation of mitochondrial proteins involved in β-oxidation of fatty acids, resulting in decreased nuclear localization of nuclear factor κB. Attenuated nuclear factor κB signaling leads to increased susceptibility to myocyte apoptosis, eosinophil chemoattractant production, and eosinophil accumulation and activation. Overall, CAPN3 acts as a gatekeeper that preserves the integrity of muscle cells.

Based on genetic association and tissue-specific expression of CAPN14 in the esophagus, dysregulated expression of CAPN14 (either increased or decreased) is associated with the development of EoE.

The CAPN14 gene is dynamically upregulated by the two related proallergic TH2 cytokines IL-4 and IL-13, which share a common subunit (IL-4 receptor α) in their receptor complexes (Wynn TA 2003). IL-13 stimulation of EPC2-immortalized esophageal epithelial cells leads to a 100-fold increase in the relative expression of CAPN14 while stimulation of IL-4 in conjunctival epithelial cells leads to a 4- to 22-fold upregulation of CAPN14 (Ueta M et al. 2010).

Remarkably, the induction effect of IL-13 in esophageal epithelial cells is specific for CAPN14, as other calpains are not induced by this interleukin. The kinetics of IL-13-induced CAPN14 expression is rapid and parallels the induction of CCL26 (eotaxin-3), a distinctly induced IL-13 upregulated gene product (Davis BP et al. 2016).

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