Endocrine Abstracts

A significant portion of intercellular communication depends on protein secretion and interpretation of extracellular signals by transmembrane receptors. Proteins of both classes fold into their functional state in the lumen of the endoplasmic reticulum (ER), a process that is assisted by a dedicated machinery of ER-associated chaperones, enzymes and other components. The magnitude of this apparatus is matched to the load of unfolded proteins confronting the ER by a cell autonomous signalling pathway referred to as the Unfolded Protein Response. The biological significance of the unfolded protein stress (ER stress) that the UPR counteracts is attested to by the deleterious consequences of mutations in signalling components of the UPR or in elements of the ER protein folding machinery. The study of extreme cases of failure of protein folding homeostasis in the secretory pathway has revealed its impact on endocrine signalling, with the endocrine pancreas manifesting special susceptibility. Of potentially greater clinical significance are hints that long term exposure to low levels of ER stress may contribute to attrition in secretory function, which may play a role in common forms of diabetes mellitus. Intriguingly, factors that influence protein folding homeostasis in the ER also have an evolutionarily-conserved dialectic relationship with intermediary metabolism and with its hormonal control. This is reflected in the influence of nutrient availability on protein folding in the ER and in an overlap between the readouts of the mammalian UPR and that of other pathways detect nutrient sufficiency. In this talk I will attempt to summarize the aforementioned relationships and discuss their physiological and pathophysiological significance.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.