Endoplasmic reticulum quality control and congenital pathology

Quality control of the endoplasmic reticulum plays a critical role in protein folding, modification and modification of a secretory pathway. As endoplasmic reticulum chaperones, calreticulin and calnexin have similar substrate specificity and share several common features. Yet, surprisingly, mice bearing a disruption in the calreticulin gene die from a lesion in cardiac development and develop significant metabolic problems whereas calnexin-deficient mice are born alive with, yet not understood, neurological problems. Studies with calreticulin and calnexin gene knockout mice and calreticulin- and calnexin-deficient cell lines indicate that calnexin is unable to compensate for the loss of calreticulin and conversely, calreticulin cannot compensate for the loss of calnexin. Calreticulin or calnexin deficiency or reduction in the level of ERp57 protein (ERp57 heterozygote mice) leads to development of metabolic disorders as documented by sever changes serum lipids and carbohydrates composition in these animals. These observations indicate that calreticulin, calnexin and ERp57, in addition of being involved in maturation of glycoproteins in the endoplasmic reticulum, perform other distinct functions including affecting energy metabolism.