The calpain system as a modulator of stress/damage response

Ubiquitously expressed mu- and m-calpain proteases consist of 80-kDa catalytic subunits encoded by the Capn1 and Capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the calpain small 1 (Capns1) gene. The mu- and m-calpain proteases have been implicated in both pro-or anti-apoptotic functions. We have found that Capns1 depletion is coupled to increased sensitivity to increased sensitivity to apoptosis triggered by a number of autophagy-inducing stimuli in mammalian cells. Therefore we investigated the involvement of calpains in autophagy using MEFs derived from Capns1 knockout mice and Capns1 depleted human cells as model systems. We found that autophagy is impaired in Capns1 deficient cells by immunostaining of the endogenous autophagosome marker LC3 and electron microscopy experiments. Accordingly, the enhancement of lysosomal activity and long-lived proteins degradation, normally occurring upon starvation, are also reduced. In Capns1 depleted cells ectopic LC3 accumulates in early endosome-like vesicles that might represent a salvage pathway for protein degradation when autophagy is defective. Calpain represents a promising target for cancer therapy since its activity is tightly linked to tumor progression. Indeed it is elevated during transformation, it is required for autophagy and survival of cancer cells and plays a key role in metastatic cell migration and angiogenesis.