The UPR, Cellular and Systemic Iron Homeostasis pp.145-161
Authors: (Susana J. Oliveira, Maria de Sousa, Iron Genes and the Immune System, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal, and others)
Abstract: The endoplasmic reticulum (ER) is a multifunctional organelle with major roles in the secretory pathway. More than a mere transit compartment for secretory and membrane-targeted proteins, the ER is responsible for their biosynthesis, folding, assembly and modifications. The accomplishment of such variety of functions closely depends upon the specialized luminal conditions found in the ER, namely: abundance of resident molecular chaperones and folding enzymes; high Ca2+ stores necessary for optimal function of the former members and oxidizing milieu compatible with disulphide bond formation. The accuracy of the process is ensured by stringent quality control mechanisms, coupled to ER-associated degradation (ERAD) of aberrant proteins. Operating together, both systems guarantee that only proteins whose native conformation was reached are delivered to the Golgi apparatus towards their final destinations. When this operational control fails, the cell senses and protects itself from the ensuing insult with a coordinated set of actions designated as the unfolded protein response, the UPR. The more widely known response involves induction of ER chaperones and foldases to meet the exceptional folding demands, improvement of ERAD of irreparably unfolded proteins and global suppression of translation to minimize the burden of new clients entering the ER. Recently, however, we and others have shown that the UPR influences the cell surface expression of MHC class I molecules and the transcriptional profile of iron genes with cellular and systemic regulatory roles. In this review we present the work that has revealed the ER stress-iron metabolism axis, also discussing possible implications for understanding the maintenance of cellular and systemic iron homeostasis both in physiological and pathological contexts. The review is concluded with the consideration of the implications of the wider role of the UPR in cell physiology, iron overload, inflammation and hepatic disease.
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