Abstract
Specific molecular interactions that underpin the switch between ER stress-triggered autophagy-mediated cellular repair and cellular death by apoptosis are not characterized. This study reports the unexpected interaction elicited by ER stress between the plasma membrane (PM)-localized apoptosis effector PERP and the ER Ca2+ pump SERCA2b. We show that the p53 effector PERP, which specifically induces apoptosis when expressed above a threshold level, has a heterogeneous distribution across the PM of un-stressed cells and is actively turned over by the lysosome. PERP is upregulated following sustained starvation-induced autophagy, which precedes the onset of apoptosis indicating that PERP protein levels are controlled by a lysosomal pathway that is sensitive to cellular physiological state. Furthermore, ER stress stabilizes PERP at the PM and induces its increasing co-localization with SERCA2b at ER–PM junctions. The findings highlight a novel crosstalk between pro-survival autophagy and pro-death apoptosis pathways and identify, for the first time, accumulation of an apoptosis effector to ER–PM junctions in response to ER stress.
Highlights
The p53 apoptosis effector related to PMP-22 (PERP) is a tetraspan plasma membrane (PM) protein that is involved in cell–cell adhesion and the regulation of apoptosis in many cell types[1,2,3]
As the peptide identified by mass spectrometry could not distinguish between the three isoforms, the specific interaction between PERP and SERCA2b was confirmed after HaloTag pull-down by Western blot using the isoform-specific antibody (Fig. 1b)
We showed that the threshold level of PERP protein is regulated through the action of a selective autophagy–lysosomal pathway
Summary
The p53 apoptosis effector related to PMP-22 (PERP) is a tetraspan plasma membrane (PM) protein that is involved in cell–cell adhesion and the regulation of apoptosis in many cell types[1,2,3]. PERP transcription is tightly controlled by both p53 and p63 and is induced during p53-mediated apoptosis[1,4]. Expression of PERP above a threshold level correlates with the activation and stabilization of its regulator p53 and the cleavage of both caspase 8 and Bid; PERP positively influences its own expression and mediates apoptosis engaging both the extrinsic and mitochondrial pathways[5,6]. Protein synthesis and modification in the endoplasmic reticulum (ER) are highly dependent on a high luminal Ca2+ concentration.
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