Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

Abstract

SUMMARY Imbalances in secretory proteostasis induced by genetic, environmental or aging related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) Unfolded Protein Response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well-defined, the impact of UPR activation on secretory proteostasis is only becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.

Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum

“…NAFL is a positive predictor of obesity complications, such as atherosclerosis, insulin resistance, and type 2 diabetes 5,7 . A well-studied ER response to stress derived from an increased load of misfolded proteins is the unfolded protein response (UPR), a pathway where X-box binding protein 1 (XBP1) is spliced to the active transcription factor XBP1s, which would then promote synthesis of ER chaperones to restore ER homeostasis 8,9 . However, in the liver of the genetically obese Lep−/− mice, abundance of ER chaperones does not appear to be increased 10 .…”

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

“…Differences reflected in the dynamics of JG98-mediated fold management likely encompass the chemical, biochemical and biophysical features driving assembly and differential stability of the NPC1 polypeptide fold in the different compartments of the endomembrane system. Moreover, each variant expressing cell may harbor distinct activation states of their unfolded protein response (UPR) [63,64] and heat-shock response (HSR) [26] pathways given that each variant likely presents a distinct folding problem leading to unique tuning of the maladaptive stress response (MSR) [24] that could further impact the response to JG98. Despite these complexities, the dynamic temporal and spatial relationships that dictate the SCV tolerance of the fold for a given environment reveal the impact of a variant on its functional-structure [2], each residue of which can be assigned a quantitative SCV setpoint value in the phenotype landscape.…”

ER Proteostasis Regulators Reduce Amyloidogenic Light Chain Secretion Through an On-Target, ATF6-Independent Mechanism

“…59 increases extracellular populations of amyloidogenic LCs available for concentration-dependent aggregation 69 into the toxic oligomers and amyloid fibrils implicated in AL pathogenesis . 70 Enhancing ER proteostasis through mechanisms such as activation of the unfolded protein response 71 (UPR)-associated transcription factor ATF6 can selectively reduce the secretion and toxic aggregation of 72 destabilized, amyloidogenic proteins (Kelly, 2020, Plate & Wiseman, 2017). ATF6 induces the expression of 73 many ER proteostasis factors including the ATP-dependent ER HSP70 BiP and multiple protein disulfide 74 isomerases (PDIs) (Haze, Yoshida et al, 1999, Shoulders, Ryno et al, 2013.…”