Diseases Originating from Altered Protein Quality Control in the Endoplasmic Reticulum

Mieko      Otsu; Roberto      Sitia

Abstract

A challenging question in biology is how cells control their shape and volume. The relative abundance of organelles can be radically modified to comply with a new task, an example being the massive development of the endoplasmic reticulum (ER) in Ig-secreting plasma cells. The ER is the site where secretory proteins are made and folded. Remarkably, it can discriminate between native and non-native proteins, restricting transport to the former, whilst retaining and eventually degrading the latter (quality control). Recent studies revealed that certain components of the unfolded protein response (UPR), a multidimensional signalling pathway originally discovered in cells exposed to severe ER stress, are crucial for the normal development of secretory cells. According to the cell types, different arms of the UPR are required: the IRE1-XBP1 pathway is essential for plasma cell differentiation, whilst the PERK-eIF2α pathway is essential for pancreatic β cells survival. Therefore, the UPR is far from being a monolithic response. Disturbances in the signalling pathways that allow the ER to satisfy the changing demand of protein synthesis can occur at various levels and often cause diseases. Here we summarize the molecular mechanisms underlying this variegated and constantly growing class of pathological conditions, focusing on diseases that are linked to alterations in the quality control functions that the ER exerts over its protein products.

Keywords: Endoplasmic reticulum, quality control, ER proliferation, UPR, ER storage disease, transport, aggregation, ERAD