Excessive nitric oxide (NO) production in cytokine-activated  cells has been implicated in  cell disruption in type 1 diabetes.  cells are very vulnerable to NO-induced apoptosis. However, the mechanism underlying this phenomenon is unclear. Low concentrations of NO that lead to apoptosis apparently do not cause severe DNA damage in mouse MIN6  cells. CHOP, a C͞EBP homologous protein that is induced by endoplasmic reticulum (ER) stress and plays a role in growth arrest and cell death, was induced by a NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP). SNAP increased cytosolic Ca 2؉ , and only agents depleting ER Ca 2؉ induced CHOP expression and led to apoptosis, suggesting that NO depletes ER Ca 2؉ . Overexpression of calreticulin increased the Ca 2؉ content of ER and afforded protection to cells against NO-mediated apoptosis. Furthermore, pancreatic islets from CHOP knockout mice showed resistance to NO. We conclude that NO depletes ER Ca 2؉ , causes ER stress, and leads to apoptosis. Thus, ER Ca 2؉ stores are a new target of NO, and the ER stress pathway is a major mechanism of NO-mediated  cell apoptosis.
Terminally misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytoplasm and degraded by proteasomes through a mechanism known as ER-associated degradation (ERAD). EDEM, a postulated Man8B-binding protein, accelerates the degradation of misfolded proteins in the ER. Here, EDEM was shown to interact with calnexin, but not with calreticulin, through its transmembrane region. Both binding of substrates to calnexin and their release from calnexin were required for ERAD to occur. Overexpression of EDEM accelerated ERAD by promoting the release of terminally misfolded proteins from calnexin. Thus, EDEM appeared to function in the ERAD pathway by accepting substrates from calnexin.
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