Abstract
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Highlights
Introduction Theendoplasmic reticulum (ER) is the site of synthesis, folding, and posttranslational modification of secretory and membranebound proteins[1]
As Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to ER stress[8,9,10], in this current study we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics
Since IAP proteins have been implicated in regulating the ER stress response[8,9,10], the present study investigated the question as to whether or not small-molecule Smac mimetics that antagonize IAP proteins affect the unfolded protein response (UPR) and ER stress-induced apoptosis
Summary
Introduction TheER is the site of synthesis, folding, and posttranslational modification of secretory and membranebound proteins[1]. Under excessive ER stress, persistent accumulation of misfolded proteins and prolonged activation of UPR promotes cell death typically via apoptosis[1]. IAP proteins, for example, cIAP1, cIAP2, and X-linked IAP (XIAP), play a key role in the regulation of cell death and survival signaling and are aberrantly expressed in many human cancers[4]. Besides preventing the interaction of XIAP with caspases, Smac mimetics stimulate autoubiquitination of cIAP1 and cIAP2 followed by their proteasomal degradation[5,6]. This leads to activation of the transcription factor NF-κB, expression of NF-κB target genes such as tumor necrosis factor α (TNFα) and TNFα-dependent cell death[5,6]. As IAP proteins have been implicated in cellular adaptation to ER stress[8,9,10], in this current study we investigated the regulation of ER stress-induced apoptosis by small-molecule Smac mimetics
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