Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease

Abstract

Systemic amyloid diseases are characterized by the deposition of an amyloidogenic protein as toxic oligomers and amyloid fibrils on tissues distal from the site of protein synthesis. Traditionally, these diseases have been viewed as disorders of peripheral target tissues where aggregates are deposited, and toxicity is observed. However, recent evidence highlights an important role for endoplasmic reticulum (ER) proteostasis pathways within tissues synthesizing and secreting amyloidogenic proteins, such as the liver, in the pathogenesis of these disorders. Here, we describe the pathologic implications of ER proteostasis and its regulation on the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Furthermore, we discuss the therapeutic potential for targeting ER proteostasis to reduce the secretion and toxic aggregation of amyloidogenic proteins to mitigate peripheral amyloid-associated toxicity involved in the onset and progression of systemic amyloid diseases.

Stress-responsive regulation of extracellular proteostasis

“…Similar results were observed in mouse models of TTR amyloid disease, where age-dependent deposition of TTR aggregates in the heart correlated with aberrant expression of proteostasis factors in the liver (Buxbaum et al, 2012). These results, and others discussed in previous reviews (Plate and Wiseman, 2017;Romine and Wiseman, 2020), highlight the important role of ER quality control in dictating both the amount and conformational integrity of proteins secreted into extracellular environments.…”

“…1). These pathways comprising chaperones, folding enzymes, and degradation factors engage nonnative proteins and facilitate their refolding and/or degradation in the early secretory pathway or extracellular environments (Wyatt et al, 2013;Plate and Wiseman, 2017;Sun and Brodsky, 2019;Chaplot et al, 2020;Romine and Wiseman, 2020;Satapathy and Wilson, 2021a;Satapathy and Wilson, 2021b). In response to stress, the composition and activity of ER and extracellular proteostasis pathways are regulated through the activity of multiple different stress-responsive signaling pathways.…”

“…Secreted proteins are targeted to the ER cotranslationally by N-terminal targeting sequences, which are proteolytically removed upon entry into the ER lumen (Plate and Wiseman, 2017;Sun and Brodsky, 2019;Romine and Wiseman, 2020). In the ER, these proteins engage ATP-dependent ER chaperoning pathways, folding enzymes (e.g., protein disulfide isomerases [PDIs]), and lectin-based chaperones (e.g., calnexin/ calreticulin) to facilitate their folding into native 3D conformations (Plate and Wiseman, 2017;Sun and Brodsky, 2019;Romine and Wiseman, 2020). Once folded, proteins are trafficked from the ER to the Golgi in a coat protein complex II (COPII)-dependent manner and subsequently directed to downstream secretory environments such as the extracellular space.…”

“…Once folded, proteins are trafficked from the ER to the Golgi in a coat protein complex II (COPII)-dependent manner and subsequently directed to downstream secretory environments such as the extracellular space. Proteins unable to attain a folded conformation through interaction with ER folding pathways are instead recognized by ER-localized factors that direct these proteins to degradation by the proteasome via ER-associated degradation (ERAD) or the lysosome through autophagic mechanisms such as ER-phagy (Plate and Wiseman, 2017;Sun and Brodsky, 2019;Romine and Wiseman, 2020). The partitioning of proteins between ER folding and degradation is a process referred to as ER quality Figure 1.…”

The 2021 FASEB Virtual Catalyst Conference on Extracellular and Organismal Proteostasis in Health and Disease, February 3‐4, 2021

“…Pharmacologically targeting either the amyloidogenic protein within the ER or the ER proteostasis environment itself improved the quality of secreted proteins reducing the toxic extracellular aggregation of amyloidogenic proteins implicated in disease. These findings highlight the importance of the ER in the pathogenesis of systemic amyloid disease and define a therapeutic strategy that can be broadly applied to mitigate the pathologic extracellular aggregation of proteins implicated in diverse protein aggregation disorders 5 …”