Aside from their important role in apoptosis, caspases also play an important role in inflammatory processes. Humans express four inflammatory caspases: Caspase-1, -4, -5, and -12. Caspase-12 is a 48 kDa protein localized to the ER and involved in the ER stress response. Caspase-12 contains a caspase-associated recruitment domain (CARD) and two catalytic domains, p20 and p10 (1). The ER stress response is important for maintaining ER homeostasis to allow proper lipid synthesis, calcium storage, and protein folding and maturation. The ER stress response is also known as the unfolded protein response (UPR) and ultimately results in apoptosis. The UPR can be triggered by two mechanisms- a transcription factor-dependent pathway or a caspase-dependent pathway. Caspase-12 plays an important role in carrying out the caspase-dependent UPR. Upon activation of the UPR, caspase-12 translocates from the ER to the cytosol and cleaves caspase-9, which in turn cleaves and activates effector caspase-3 (2).
Nakagawa et. al. used the Caspase-12 antibody to elucidate a mechanism for procaspase-12 activation in the ER stress response (3). Given their role as cysteine proteases and overlapping activity with caspases, the group investigated calpains as potential activators of caspase-12. First, they used the Caspase-12 antibody to determine the tissue distribution and cellular localization of caspase-12. The group demonstrated the caspase-12 is ubiquitously expressed in all of the murine tissues they assessed. Cellular localization studies with the Caspase-12 antibody showed that caspase-12 expression was restricted to the cytoplasmic face of the ER. The group then exposed their cells to oxygen and glucose deprivation to initiate the UPR. They used western blot and the Caspase-12 antibody to assess the size of cleaved Caspase-12 fragments with and without calpain inhibitors. The Caspase-12 antibody recognized only one uncleaved procaspase-12 band when cells were treated with calpain inhibitors. The group proposed that m-Calpain cleaves the CARD domain from procaspase-12 in a calcium-dependent mechanism, releasing the catalytic subunits of caspase-12. This mechanism is important for better understanding the physiologic important of the UPR as well as the pathologic derangements seen in conditions like Alzheimer’s, Huntington’s, and Parkinson's.
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