Stress-responsive regulation of extracellular proteostasis

Abstract

Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.

ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion Through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors

“…Stress-independent activation of ATF6 has emerged as a promising approach to reduce secretion and subsequent aggregation of amyloidogenic proteins such as TTR. [13][14][15] However, the molecular basis for ATF6dependent reductions in amyloidogenic TTR secretion was previously poorly understood. Here, we demonstrate that ATF6 activation decreases secretion of a destabilized, amyloidogenic TTR variant through a mechanism involving increased interactions with ATF6-regulated ER chaperones and folding factors including BiP and PDIA4 that retain the aggregation prone TTR within the ER.…”

“…An attractive strategy to mitigate pathologic TTR aggregation is through adaptive remodeling of the endoplasmic reticulum (ER) to reduce secretion and subsequent aggregation of destabilized TTR variants. [13][14][15] The ER is the first organelle of the secretory pathway responsible for the folding and trafficking of secretory proteins including TTR. In the ER, secretory proteins engage ER-localized protein homeostasis (or proteostasis) factors including chaperones, folding enzymes, and degradation factors that facilitate their partitioning between biological pathways involved in protein folding, trafficking and degradation -a process referred to as ER quality control.…”

“…Transcriptional remodeling of ER protein folding, trafficking, and degradation pathways induced by the UPR-associated transcription factors XBP1s (activated downstream of IRE1) and ATF6f (a cleaved product of ATF6) adapt the relative capacities of ER quality control pathways to maintain secretory integrity in response to genetic, environmental, or aging-related stress. 15 Alternatively, PERK signaling influences ER quality control through multiple mechanisms including reductions of ER protein folding load downstream of PERK-induced, eIF2a phosphorylation-dependent translational attenuation. 15 This ability to adapt ER quality control through PERK, IRE1/XBP1s, and/or ATF6 signaling provides a critical mechanism to selectively enhance secretory proteome integrity and protect downstream secretory environments in response to ER stress.…”

“…15 Alternatively, PERK signaling influences ER quality control through multiple mechanisms including reductions of ER protein folding load downstream of PERK-induced, eIF2a phosphorylation-dependent translational attenuation. 15 This ability to adapt ER quality control through PERK, IRE1/XBP1s, and/or ATF6 signaling provides a critical mechanism to selectively enhance secretory proteome integrity and protect downstream secretory environments in response to ER stress. ER stress and UPR signaling have an important role in regulating ER quality control and extracellular aggregation of TTR.…”

The Emerging Roles of Extracellular Chaperones in Complement Regulation

“…Molecular chaperones, proteins that assist in protein folding and prevent undesirable protein–protein interactions, are key players in intracellular proteostasis. However, some chaperones are constitutively secreted into the extracellular milieu [ 1 , 2 , 3 ]. In addition to roles in controlling undesirable protein–protein interactions and the clearance of extracellular misfolded proteins, these extracellular chaperones (ECs) also exert effects on the immune system.…”