Endoplasmic reticulum quality control and systemic amyloid disease: Impacting protein stability from the inside out

Abstract

The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking, and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them toward ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion, and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the unfolded protein response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease.

Keywords: chaperones; protein folding; stress-activated signaling.

Figure 1. Secretion of proteins through the secretory pathway is dependent on the relative activity of ER protein folding, trafficking and degradation pathways

A. Illustration showing the partitioning of ER-targeted proteins between ER protein folding, trafficking and degradation pathways. B. Plot relating the secretion efficiency from mammalian cells to the inherent energetic stability for a series of destabilized variants of a single protein. The impact of increasing ER folding capacity (green) or degradation capacity (red) on the secretion of these variants is also shown.

Figure 2

Illustration showing the signaling pathways activated downstream of the three UPR sensor proteins PERK, IRE1 and ATF6.

Figure 3. Illustration showing the therapeutic potential for UPR-dependent adaptation of ER quality control to attenuate secretion of destabilized, aggregation-prone proteins

In disease pathophysiology (left), destabilized proteins are folded and efficiently secreted. The efficient secretion of these proteins increases their extracellular concentrations available for proteotoxic aggregation and distal deposition involved in disease pathogenesis. UPR-dependent remodeling of ER quality control pathways (right) can reduce secretion of these destabilized proteins through increased ER retention or increased partitioning to degradation pathways. This reduced secretion decreases extracellular populations of destabilized, aggregation-prone protein available for proteotoxic aggregation and attenuates the distal proteotoxicity causatively associated with systemic amyloid disease pathogenesis.