Interplay Between the Oxidoreductase PDIA6 and microRNA-322 Controls the Response to Disrupted Endoplasmic Reticulum Calcium Homeostasis

Abstract

The disruption of the energy or nutrient balance triggers endoplasmic reticulum (ER) stress, a process that mobilizes various strategies, collectively called the unfolded protein response (UPR), which reestablish homeostasis of the ER and cell. Activation of the UPR stress sensor IRE1α (inositol-requiring enzyme 1α) stimulates its endoribonuclease activity, leading to the generation of the mRNA encoding the transcription factor XBP1 (X-box binding protein 1), which regulates the transcription of genes encoding factors involved in controlling the quality and folding of proteins. We found that the activity of IRE1α was regulated by the ER oxidoreductase PDIA6 (protein disulfide isomerase A6) and the microRNA miR-322 in response to disruption of ER Ca2+ homeostasis. PDIA6 interacted with IRE1α and enhanced IRE1α activity as monitored by phosphorylation of IRE1α and XBP1 mRNA splicing, but PDIA6 did not substantially affect the activity of other pathways that mediate responses to ER stress. ER Ca2+ depletion and activation of store operated Ca2+ entry reduced the abundance of the microRNA miR-322, which increased PDIA6 mRNA stability and consequently IRE1α activity during the ER stress response. In vivo experiments with mice and worms showed that the induction of ER stress correlated with decreased miR-322 abundance, increased PDIA6 mRNA abundance, or both. Together these findings demonstrated that ER Ca2+, PDIA6, IRE1α, and miR-322 function in a dynamic feedback loop modulating the UPR under conditions of disrupted ER Ca2+ homeostasis.

The P5 disulfide switch: taming the aging unfolded protein response

“…The seemingly contradictory findings regarding the role of P5 in activating and deactivating these responses (Eletto et al 2014;Groenendyk et al 2014) warrant further investigation and may hold the key to unlocking the role of this protein in various pathological conditions. Another important target for study with regard to P5 is the effects of the localization of this protein in the mitochondria and the consequences, if any, of these effects on the activation of the UPR.…”

“…However, recent discoveries regarding the role of this protein in regulating the PERK and IRE-1 (Eletto et al 2014;Groenendyk et al 2014) UPR arms provide a more comprehensive and convincing explanation to the perceived effects of this protein in the aforementioned pathologies. This interaction may hold the key to better understanding the observations linking P5 to UPRassociated cell death.…”

“…Furthermore, it was shown that the initial IRE-1 response observed in cells overexpressing P5 was incomplete relative to wild-type cells (Groenendyk et al 2014), suggesting that P5 may be playing both sides by deactivating the IRE-1 and PERK responses via a thiol-based interaction on one hand, while promoting the activation of the UPR by stimulating NOX-associated ROS generation on the other. Further study regarding the localization of P5 during ER stress, and the effect of NOX-associated UPR activation may help further elucidate the effect of P5 on the UPR and resolve these findings.…”

“…Recent findings regarding regulation of cellular UPR by the P5 disulfide isomerase (Eletto et al 2014;Groenendyk et al 2014) and its discovery in various age-related pathologies have provided new potential targets with regard to regulation of the UPR. This review discusses these findings and attempts to bridge these discoveries and highlight the importance of P5 as an important target for aging research.…”

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells

“…7B). Other key UPR genes, such as those encoding the chaperones Hspa5 (Grp78 or BiP) and Pdia6 (Groenendyk et al, 2014;Lee, 2005), were also upregulated in Setdb1-deficient pro-B cells (Fig. 7B).…”