Abstract
Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR). The UPR aims at restoring ER homeostasis; if the ER stress cannot be resolved, apoptosis is triggered. However, the mechanisms responsible for regulating the balance between cell life and death decisions that occur after exposure to ER stress remain unclear. Protein kinase D1 (PKD1) has been reported to initiate protective signaling against oxidative stress or ischemia, two conditions that impinge on the induction of ER stress. In addition, the high levels of expression of PKD1, observed in highly proliferative cancers and tumors with poor prognosis, contribute to enhanced resistance to chemotherapy. In this study, we show that the ER stress inducers tunicamycin and thapsigargin lead to the activation of PKD1 in human prostate cancer PC-3 cells and in hepatoma HepG2 cells through a PKCδ-dependent mechanism. Moreover, our data indicate that PKD1 is required for the stabilization of inositol-requiring enzyme 1 (IRE1) and the subsequent regulation of its activity. PKD1 activation contributes to the phosphorylation of mitogen-activated protein kinase phosphatase 1, resulting in decreased IRE1-mediated c-Jun N-terminal kinase activation. This study unveils the existence of a novel PKD1-dependent prosurvival mechanism that is activated upon ER stress and selectively enhances IRE1 prosurvival signaling.
Highlights
Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR)
Considering its ability to modulate the kinetics of Jun N-terminal kinase (JNK) signaling, Protein kinase D (PKD) may function in balancing UPR signaling, thereby determining cell fate
To further confirm that ER stress mediates the activation of Protein kinase D1 (PKD1), we evaluated the phosphorylation status of putative PKD substrates using phospho-(Ser/Thr) PKD substrate antibodies
Summary
Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR). The UPR is mediated by three different ER stress sensors, including inositol-requiring enzyme 1 (IRE1), protein kinase R–like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) [4]. JNK signaling is required for the transition from the protective to pro-apoptotic function of the UPR [14] This indicates that IRE1 RNase activity (XBP1 splicing) and its kinase activity (JNK signaling activation) play a differential role in the regulation of cell survival. PKD1 activation is responsible for regulating JNK signaling by modulating mitogen-activated protein kinase phosphatase 1 (MKP1) phosphorylation, which turns off the pro-apoptotic effect of JNK signaling in the UPR. This study, provides evidence for the role of PKD1 in the control of selective IRE1 prosurvival signaling
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