TRAILR2/DR5-Mediated Activation of Apoptosis upon Endoplasmic Reticulum Stress: History
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Subjects: Biochemistry & Molecular Biology
Contributor:
Rocío Mora-Molina
,
Abelardo López-Rivas

The uncontrolled proliferation of malignant cells in growing tumors results in the generation of different stressors in the tumor microenvironment, such as nutrient shortage, hypoxia, and acidosis, among others, that disrupt endoplasmic reticulum (ER) homeostasis and may lead to ER stress. As a response to ER stress, both normal and tumor cells launch a set of signaling pathways known as the unfolded protein response (UPR) to restore ER proteostasis and maintain cell viability and function. However, under sustained ER stress, an apoptotic cell death process can be induced and this has been the subject of different reviews articles, although the role of the (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5)-activated extrinsic pathway of apoptosis has not yet been thoroughly summarized. In this review, we focus on the regulation of TRAIL-R2/DR5-induced apoptosis in tumor cells undergoing ER stress with a special interest in how the levels of FLICE-like inhibitory protein (FLIP) can determine cell fate.

  • apoptosis
  • TRAILR2/DR5
  • endoplasmic reticulum stress
  • unfolded protein response

1. Introduction

The endoplasmic reticulum (ER) is a highly dynamic compartment with a wide variety of functions; of these, Ca2+ storage and homeostasis or lipid biosynthesis are associated with smooth ER. Nevertheless, a key function of the ER is to control proteostasis, which is mainly linked to rough ER [1]. Indeed, the ER is responsible for at least one-third of all protein synthesis, folding, assembly, trafficking and degradation. Those proteins whose fate is to follow the secretory pathway enter in the ER through the translocon complex. Once in the ER, the nascent protein chains are modified and properly folded by chaperones, peptidylprolyl isomerases, protein disulfide isomerases, oxidoreductases or glycosyltransferases. The oxidizing environment of the ER along with a high concentration of Ca2+ specifically promotes the creation of disulfide bonds and chaperone action, respectively. After being correctly folded, proteins are translocated to the Golgi apparatus; then, they are directed to different organelles, the plasma membrane or the extracellular space. Those proteins that are not properly folded or aggregated are sent to the cytosol in order to be ubiquitinated and degraded by the proteasome through a process called ER-associated protein degradation (ERAD) [2]. 
Although protein folding and transport are tightly regulated in the ER, there are scenarios, such as a high protein synthesis demand and changes in the Ca2+ levels or redox status, that alter ER homeostasis and provoke an excess of misfolded or/and unfolded proteins to appear, a situation known as ER stress. These alterations appear in either physiological (processes accompanied by an increase in protein demand such as proliferation and development of secretory cells, such as plasma B cells or pancreatic β cells) or pathological (hypoxia, inflammation or nutrient deprivation) situations [3][4]. To restore proteostasis upon ER stress, several signaling pathways called unfolded protein response (UPR) become activated. Initially, UPR signaling leads to the inhibition of global protein synthesis and the degradation of unfolded and misfolded proteins. Subsequently, the protein folding capacity of the ER increases by the transcriptional regulation of numerous genes in charge of controlling proteostasis. However, if ER stress is unresolved, the UPR triggers signaling pathways that activate apoptotic cell death through the extrinsic, the intrinsic or both apoptotic pathways. Hence, the UPR determines the cell fate according to the duration and intensity of ER stress [3].

2. UPR Signaling Branches

In mammals, the following three main stress sensors are found in the ER membrane: protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring protein 1 (IRE1α/β) and activating transcription factor 6 α (ATF6α) (Figure 1). 
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Figure 1. Three ER stress sensors and the induction of the UPR. RIDD: IRE1-α-dependent decay; RPAP2: RNA polymerase II-associated protein 2 phosphatase; S1P: serine protease site-1 protease; S2P: metalloprotease site-2 protease. In mammals, three main stress sensors are found in the ER: Protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring protein 1 (IRE1α/β) and activating transcription factor 6 α (ATF6α). Under unstressed situations, all of them are inactive through the binding to BiP in ER lumen. When improperly folded proteins appear, BiP dissociates from ER stress sensors and binds unfolded and misfolded proteins. BiP dissociation from ER stress sensors allows the activation of the unfolded protein response.

2.1. IRE1α Pathway

IRE1 is the most conserved arm of the UPR and it was first identified in budding yeast [9]. In mammalian cells, IRE1 is encoded by two genes: IRE1A and IRE1B, leading to IRE1α and IRE1β protein expression, respectively. While IRE1A is constitutively expressed in all cell types, IRE1B expression is limited to intestine and lung epithelial cells [10]. Because IRE1α is ubiquitously found, we referred solely to it in this review. IRE1α is a type I transmembrane protein, with cytosolic Ser/Thr kinase and endoribonuclease (RNase) domains. Following BiP dissociation and/or the binding of misfolded proteins at the ER luminal domain [11][12], IRE1α oligomerizes, which allows activation through trans-autophosphorylation. These events create conformational changes that activate the IRE1α endoribonuclease domain, which induces the cleavage of the 26-nucleotide intron from X-box-binding protein 1 (XBP1) mRNA. Unspliced XBP1 (XBP1u) protein lacks functional activity and is highly unstable and quickly degraded. In contrast, spliced XBP1 (XBP1s) mRNA codes for a stable transcription factor [13][14]. Once in the nucleus, XBP1s upregulates the expression of genes encoding protein folding, ERAD, and protein quality control components. In addition, XBP1s promotes the transcription of genes related to phospholipid synthesis to expand ER membranes during ER stress.

2.2. PERK Pathway

Similar to IRE1α, PERK is another type I transmembrane protein with a cytosolic Ser/Thr kinase domain [15]. Once PERK is released from BiP and/or associates with misfolded proteins in its ER luminal domain [11][16], it is activated by oligomerization and trans-autophosphorylation. Then, PERK phosphorylates the alpha subunit of eukaryotic initiator factor 2 (eIF2α) at S51, leading to the inhibition of 5′-cap dependent protein translation [15]. Overall, this mechanism decreases the protein synthesis rate to restore ER homeostasis. However, although general protein translation is prevented, specific mRNAs can still be translated. These mRNAs harbor upstream open reading frames (uORFs), which allow cap-independent translation in stress situations. One of these mRNAs preferentially translated upon ER stress is activating factor 4 (ATF4) with two uORFs [17][18]. ATF4 is a basic zipper (bZIP) transcription factor that along with another bZIP dimerization partner controls the transcription of genes related to the antioxidant response, amino acid metabolism or autophagy [19][20]. A key gene regulated by ATF4 is DDIT3, which encodes another transcription factor named CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP). Interestingly, CHOP has been linked to ER stress-induced apoptosis, favoring the transcription of pro-apoptotic genes, such as TRAILR2/DR5, as well as repressing the expression of anti-apoptotic BCL-2 family members during ER stress [21][22].

2.3. ATF6 Pathway

In contrast to IRE1α and PERK, ATF6α is a type II transmembrane protein harboring a bZIP in its cytosolic domain [23]. Following BiP dissociation (the binding to misfolded proteins has not been attributed to ATF6α), ATF6α moves to the Golgi apparatus where two proteases, serine protease site-1 protease (S1P) and metalloprotease site-2 protease (S2P), cleaves ATF6α, generating the ATF6 p50 N-terminal fragment, which acts as a transcription factor [24][25]. ATF6 p50 promotes the transcription of ERAD-related genes. Furthermore, ATF6 p50 can also function with XBP1s in a heterodimer to mediate the transcription of XBP1 and genes encoding protein folding enzymes and components of the ERAD pathway [26][27][28].

3. UPR Activation: Restore ER Homeostasis or Die in the Attempt

Initially, the activation of UPR signaling pathways aims to restore ER proteostasis to facilitate cell survival. However, unresolved ER stress shifts UPR signaling from adaptation to apoptotic cell death signaling. UPR kinetics can be divided into four phases [29]. First, the immediate response is initiated by decreasing the ER protein load, which occurs by inhibiting protein synthesis and degrading mRNAs through the PERK and IRE1α pathways, respectively. Second, the transcriptional phase allows the upregulation of foldases, chaperones and other proteins related to protein folding in addition to components of ERAD through the PERK, IRE1α and ATF6 pathways. Third, a transitional phase begins in which IRE1α signaling is usually attenuated, while the PERK pathway is maintained, leading to the emergence of pro-apoptotic factors. Finally, sustained ER stress triggers the apoptotic program, and the intrinsic, extrinsic or both apoptotic pathways have been reported to be activated [30][31][32][33].

3.1. IRE1α Pathway and Apoptosis

In addition to the downstream signaling previously described, upon ER stress, IRE1α serves as a scaffold for the assembly of a platform called the UPRosome at the ER membrane that modulates IRE1α activity and triggers different pathways, such as Jun amino-terminal kinase (JNK), nuclear factor-kappa B (NF-kB) [34][35][36]. Interestingly, the UPRosome can also mediate death receptor-independent caspase-8 activation [37]. Although IRE1α signalling is usually linked to an adaptive response, excessive or chronic ER stress can lead to prolonged RIDD, which, by degrading chaperone-encoding mRNAs such as BiP mRNA, and miRNAs, provokes cell death. 
 
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Figure 2. UPRosome platform assembled around IRE1α. Signaling pathways activated following formation of the multi-protein complex named the UPRosome.

3.2. PERK Pathway and Apoptosis

PERK-P-eIF2α-ATF4-CHOP is the UPR pathway most linked to persistent ER stress-induced apoptosis (Figure 3). The ATF4/CHOP heterodimer regulates the expression of a battery of target genes with important roles in cell death upon ER stress. One of these genes codes GADD34, the regulatory subunit of protein phosphatase 1 (PP1), which, in a situation of unresolved stress, dephosphorylates P-eIF2α, resulting in the recovery of global protein synthesis, which causes proteotoxicity and ROS production [38]. As previously mentioned, CHOP induces the expression of different pro-apoptotic factors, such as the BH3-only members of the BCL-2 family BIM, PUMA and NOXA, TRAILR2/DR5 and TRB3, and represses the expression of the anti-apoptotic protein BCL-2 [10]. In addition, CHOP has been linked to ROS production in the ER, likely through the transcriptional induction of ER oxidase 1α (ERO1α) [39][27]. 

Recently, the crosstalk between the PERK and IRE1α branches of the UPR has been described [40]. During the adaptive phase of the UPR, both pathways become activated to restore ER proteostasis. The endoribonuclease activity of IRE1α mediates RIDD of TRAILR2/DR5 mRNA, promoting cell survival. However, after prolonged ER stress, IRE1 signalling is attenuated, and the PERK pathway ultimately leads to apoptosis [41]. During the terminal phase of the UPR, RNA polymerase II-associated protein 2 (RPAP2) phosphatase acts downstream of PERK to attenuate IRE1 signalling, allowing TRAILR2/DR5 mRNA translation and the execution of apoptosis via the extrinsic pathway [40].

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Figure 3. PERK pathway in apoptosis induction. Upon ER stress, PERK activation results in the inhibition of global protein synthesis. At the same time, translation of ATF4 transcription factor will in turn lead to induction of CHOP. ATF4/CHOP heterodimer will be responsible for the upregulation of different genes involved in the control of cell death by apoptosis.

3.3. ATF6 Pathway and Apoptosis

The ATF6 branch of the UPR is probably less related to the regulation of apoptosis than the IRE1α and PERK arms. Nevertheless, upon the activation of ATF6 by proteolysis in the Golgi apparatus, ATF6 p50 can bind the DDIT3 promoter and contribute to regulating the expression of CHOP during ER stress [42], which can provoke the death of the cell by apoptosis. 

4. Role of the TRAIL-R2-Activated Extrinsic Apoptotic Pathway in the Control of Tumor Progression

4.1. TRAIL-R2 Upregulation in Cells Undergoing ER Stress

In conventional two-dimensional cultures of tumor cells, ER stress-inducing agents have been shown to activate the extrinsic apoptotic pathway through the PERK pathway-mediated induction of the CHOP transcription factor, leading to the upregulation of TRAILR2/DR5 expression [43], which induces the activation of caspase-8 at an intracellular DISC [31][43][44]. Interestingly, DISC assembly under these stressed conditions occurs independently of the TRAIL ligand. Instead, TRAILR2/DR5 clustering is induced by its binding to exposed hydrophobic residues on misfolded proteins at the ER-Golgi intermediate compartment [45]. Collectively, these results demonstrate that the extrinsic pathway of apoptosis plays a relevant role in the terminal UPR. Other stimuli that disrupt protein folding, such as glucose or glutamine deprivation, also cause TRAILR2/DR5 upregulation and caspase-8-dependent cell death [46][47].

4.2. Role of Cellular FLICE-like Inhibitory Protein (FLIP) in Apoptosis Regulation upon ER Stress

The FLIP long (FLIPL) and FLIP short (FLIPS) protein levels play a crucial role in controlling the extrinsic pathway of apoptosis triggered upon TRAILR2/DR5 activation by its ligand [48][49][50][51]. Furthermore, both in vitro and in vivo studies have revealed the survival role of FLIPL/S in the viability of colon cancer cells by inhibiting chemotherapy-induced apoptosis [52]. In addition to the canonical role of FLIP splice isoforms as regulators of DISC-dependent caspase-8 activation at the plasma membrane, it was recently reported that FLIPL localizes to the ER in MEFs, where it was shown to inhibit the caspase-8-mediated cleavage of an ER-localized protein substrate [53]. Interestingly, recent data have revealed that TRAILR2/DR5 upregulation and apoptosis in 2D cultures of colon tumor cells undergoing ER stress are preceded by an early decrease in the protein levels of both FLIP isoforms, which alters the caspase-8/FLIP ratio, facilitating caspase-8 activation at the intracellular DISC and the subsequent induction of apoptosis [54], as has been demonstrated in TRAIL-induced apoptosis [49][50]. Collectively, these results suggest that FLIP proteins play a key role in controlling cell fate decisions upon ER stress in cancer cells (Figure 4).
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Figure 4. TRAILR2/DR5 upregulation and FLIP downregulation are both required for ER stress-induced apoptosis. ERGIC: ER-Golgi intermediate compartment. CHOP-induced TRAIL-R2/DR5 upregulation and a decrease in the expression levels of cFLIP proteins upon ER stress, which alters the caspase-8/FLIP ratio, facilitate caspase-8 activation and apoptosis.
Multicellular tumor spheroids (MCTSs) closely mimic the properties of solid tumors and represent an intermediate stage between conventional two-dimensional cultures and in vivo models. Growing MCTSs contain a heterogeneous cell population comprising proliferative cells surrounding quiescent cells and a necrotic core [55]. During spheroid growth, the inner layers of cells undergo nutrient and oxygen shortages in addition to the accumulation of cellular waste, causing metabolic changes and leading to a quiescent phenotype in the intermediate layers and cell death in the deepest layers, similar to that observed in solid tumors. Indeed, spheroids beyond a diameter of 500 μm resemble avascular microtumors or micrometastases of cancer patients [56]. MCTSs are markedly more resistant to ER stress than 2D cultures of tumor cells. Interestingly, tumor spheroids maintain the FLIPL levels during persistent ER stress despite activation of the PERK-ATF4-CHOP branch of the UPR and upregulation of the TRAILR2/DR5 protein levels [54]. These data identify the deregulation of the mechanisms controlling the FLIPL levels [57] in spheroid cultures as an essential event in the process leading to apoptosis inhibition under chronic ER stress (Figure 5).
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Figure 5. Schematic representation of the differential apoptosis induction between 2D and 3D cell cultures. Despite a similar increase in TRAIL-R2/DR5 levels in 2D and 3D cultures upon ER stress, FLIP levels are maintained in the latter, thus preventing caspase-8 activation of apoptosis.

5. Conclusions

A high growth rate of cancer cells along with the poor vascularization of tumours result in stressful conditions in the tumour microenvironment, including a low oxygen supply and lack of nutrients, leading to metabolic stress. Metabolic stress can, in turn, adversely affect the environment of the endoplasmic reticulum (ER) and impact the maturation of nascent proteins. The resultant accumulation of the unfolded/misfolded proteins activates the UPR, which serves primarily to protect the cell during stress and helps restore homeostasis in the ER, facilitating tumour growth. However, if stress is prolonged or there is excessive stimulation of these signalling pathways, TRAILR2/DR5-mediated activation of the extrinsic apoptotic machinery and thereby cell death will occur. In this scenario, recent data suggest that cellular levels of FLIPL may play an important role in tumour cell fate decisions under the stressful conditions of the tumour microenvironment. Thus, in stressful situations, maintaining the levels of this protein that inhibits the extrinsic apoptosis pathway could enable the activation of an adaptive response in tumour cells and other tumour stromal cells, which would promote tumour growth and progression. Importantly, these results also reveal a dependence of tumour cells on maintaining FLIPL levels in the context of the tumour, which implies a vulnerability of these cells that could serve as a therapeutic target in cancer treatment.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23168987

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