ER Stress-Induced Clearance of Misfolded GPI-Anchored Proteins via the Secretory Pathway

Abstract

SummaryProteins destined for the cell surface are first assessed in the endoplasmic reticulum (ER) for proper folding before release into the secretory pathway. This ensures that defective proteins are normally prevented from entering the extracellular environment, where they could be disruptive. Here, we report that, when ER folding capacity is saturated during stress, misfolded glycosylphosphatidylinositol-anchored proteins dissociate from resident ER chaperones, engage export receptors, and quantitatively leave the ER via vesicular transport to the Golgi. Clearance from the ER commences within minutes of acute ER stress, before the transcriptional component of the unfolded protein response is activated. These aberrant proteins then access the cell surface transiently before destruction in lysosomes. Inhibiting this stress-induced pathway by depleting the ER-export receptors leads to aggregation of the ER-retained misfolded protein. Thus, this rapid response alleviates the elevated burden of misfolded proteins in the ER at the onset of ER stress, promoting protein homeostasis in the ER.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein

“…Alternatively, it may be feasible that ERp57 and PDIA1 act on different conformational pools of unfolded/ misfolded PrP, because PDIA1 is also part of the ERAD pathway (66) and may therefore target unfolded/misfolded PrP toward degradation. Of note, a recent report suggested that calnexin mediates a novel PrP clearance pathway under ER stress termed "rapid ER stress-induced export" (67). This pathway involves the export of misfolded GPI proteins to the plasma membrane for subsequent degradation by the lysosome.…”

Immunogenic cell death

“…Consistent with this view, emerging data suggest that ICD shares key danger signalling pathways with viral infection . The observation that ICD can be instigated by certain oncolytic viruses (Vacchelli et al, 2013), supports this notion.Interestingly, a recent elegant study reported that during ER stress, misfolded glycosylphosphatidylinositol-anchored proteins tend to engage an ER escape mechanism, involving the ER-export receptor Tmp21, through which they enter the secretory pathway and are temporally exported to the cell surface (Satpute-Krishnan et al, 2014). However, whether this phenomenon plays any role in the ER stress-induced DAMPs emission needs further confirmation.…”

Endoplasmic reticulum stress in brain ischemia

“…It is reported that ERAD responses are initiated more rapidly and are more reversibly than UPR, which occurs with a few hours delay that may be related to its complex activation mechanisms and the temporal lag of transcriptional response [22,23]. As a prerequisite of maintaining proteostasis, ERAD transports folding-defective proteins from the ER membrane to the cytosol, where they undergo ubiquitylation and 26S proteasome-mediated degradation [24] ( Figure 1A).…”

“…Another degradation process, which is referred to as rapid ER stress-induced export (RESET), delivers abnormal folded proteins from the ER to the lysosomes for destruction through the secretory pathway [23]. Glucosylphosphatidylinositol (GPI) anchored proteins are abundant disease-causing misfolding variants, which are poorly degraded by ERAD, and mainly eliminated by RESET [25].…”