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The endoplasmic reticulum stress response: A link with tuberculosis?
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Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW Q6
The endoplasmic reticulum stress response: A link with tuberculosis?
Q5,1
Yongyong Cui a, Deming Zhao a, Paul Barrow b, Xiangmei Zhou a, * a
Q2
The State Key Lab of Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National TSE Lab, College of Veterinary Medicine, China Agricultural University, Beijing 100193, PR China b School of Veterinary Medicine, University of Nottingham, Sutton Bonington, Loughborough, Leicestershire, Le12SRD, UK
a r t i c l e i n f o
s u m m a r y
Article history: Received 21 July 2015 Received in revised form 26 October 2015 Accepted 28 December 2015
Tuberculosis (TB) remains a major cause of mortality and morbidity in the worldwide. The endoplasmicreticulum stress (ERS) response constitutes a cellular process that is triggered by mycobacterial infection that disturbs the folding of proteins in the endoplasmic reticulum (ER). The unfolded protein response (UPR) is induced to suspend the synthesis of early proteins and reduce the accumulation of unfolded- or misfolded proteins in the ER restoring normal physiological cell function. Prolonged or uncontrolled ERS leads to the activation of three signaling pathways (IRE1, PERK and ATF6) which directs the cell towards apoptosis. The absence of this process facilitates spread of the mycobacteria within the body. We summarize here recent advances in understanding the signaling pathway diversity governing ERS in relation to TB. © 2015 Published by Elsevier Ltd.
Keywords: Tuberculosis Endoplasmic-reticulum stress (ERS) The unfolded protein response (UPR) Apoptosis Mycobacteria
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The endoplasmic reticulum stress-associated triad of pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Chaperone involvement in UPR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The IRE1a pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. The PERK pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. The ATF6 pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Ca2þ, a crucial factor in endoplasmic reticulum stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Q3
It is more than one hundred years since Mycobacterium tuberculosis (Mtb) was first characterized by Robert Koch. Tuberculosis (TB) remains one of the most serious global diseases affecting man,
* Corresponding author. Tel.: þ86 10 62734618; fax: þ86 10 62732975. E-mail addresses: [email protected] (Y. Cui), [email protected] (D. Zhao), [email protected] (P. Barrow), [email protected] (X. Zhou).
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preferentially affecting aged individuals or those affected by the human immunodeficiency virus (HIV). More than 9 million new cases were reported in 2013 with 1.5 million deaths in the world. Multi-drug resistance is a particularly intractable problem with an estimated 480,000 new cases and 210,000 deaths in 2013, of which 9.0% were reported in some countries to be infected with extensively drug resistant (XDR) strains [1]. Mtb is highly adapted to the human host and has multiple mechanisms to resist the host immune response after entry primarily through the respiratory tract. Failure of the immune
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Please cite this article in press as: Cui Y, et al., The endoplasmic reticulum stress response: A link with tuberculosis?, Tuberculosis (2016), http:// dx.doi.org/10.1016/j.tube.2015.12.009
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response to clear infection results in death of individual cells. Interestingly, cell death is a double-edged sword in the competition between host and pathogen. Necrosis favors the spread of Mtb, whereas, by contrast, apoptosis facilitates controlling the infection [2]. Bacterial killing by infected cells is mediated by the production of cytokines and intracellular enzymes which also results in autophagy. Macrophages are the major host cell type infected by Mtb. In earlier studies, Mtb is considered to resident in phagosomal compartments which immediately fuse with lysosomes after entering into the cells. Phagolysosome fusion offers an acidic environment rich in hydrolytic enzymes that degrade and kill bacteria. Whereas, in recent studies, Mtb surprisingly translocate from phagolysosomes into the cytosol in nonapoptotic cells, but not for M. bovis BCG or in heat-killed mycobacteria due to the virulent strains secreting mycobacterial gene products the 10-kDa culture
filtrate protein (CFP-10) and the 6-kDa early secreted antigenic target (ESAT-6) which have cytolytic ability [3e5]. Cytosolic Mtb has been reported to induce type I Interferons (IFNs) and to activate autophage via the stimulator of interferon gene (STING) pathway [6]. As known, STING locates in the endoplasmic reticulum (ER) membrane. Infection of macrophages by the virulent H37Rv and attenuated H37Ra strains results in increases in the amount of rough- (RER) and smooth- (SER) endoplasmic reticulum respectively [7]. ER is not only the major site of folding and transportation of proteins after synthesis, but also the major storage site of intracellular Ca2þ and of synthesis of cholesterol steroids and many lipids. Mycobacterial infection results in loss of Ca2þ from the ER and an increase in the intracellular redox state which results in accumulation of unfolded or misfolded proteins in the ER resulting
Figure 1. Cellular responses to endoplasmic reticulum stress induced by mycobacteria. Under normal physiological conditions, inactive Bip binds to the lumen domain of three kinds of transmembrane protein: inositol-requiring kinase/endoribonuclease 1 (IRE1), protein kinase activated by double-stranded RNA (PKR)-like ER kinase (PERK) and activating transcription actor 6 (ATF6). The accumulation of unfolded or misfolded proteins in the ER resulting in ER stress (ERS) when the cells are infected by Mtb or antigen proteins like ESAT-6. The Bip from IRE1, PERK and ATF6 is then able to bind unfolded-or misfolded proteins. The luminal domain of dissociated IRE1a forms homodimers in the ER membrane, while the cytosolic domain of IRE1a auto-phosphorylates to stimulate the kinase and RNase activities and to splice XBP-1 mRNA which binds to the UPR element (UPRE) and to the ER stress-response elements I and II (ERSE-I and ERSE-II) in the promoter regions of target genes. IRE1 can also recruit TRAF2 and ASK1, leading to down-stream activation of JNK and p38 MAPK when the cells are infected by M. kansasii or the Mtb 38 kDa antigen, then activates CHOP and other apoptotic transcription factors. In addition, the Mtb 38 kDa antigen can activate MAPK phosphorylation in both a TLR2-and TLR4-dependent manner. Regulated IRE1-dependent decay of mRNA (RIDD) has been shown to reduce ER localized mRNAs after Mtb infection. Activated PERK undergoes oligomerization and trans-autophosphorylation when the cells are infected by Mtb or antigen proteins like ESAT-6. PERK phosphorylates Ser51 of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) which selectively induces the expression of activating transcription factor 4 (ATF4) mRNA which can induce transcription of some ER chaperone proteins and UPR-related transcription factor genes. CHOP can activate DNA damage-inducible transcript 34 (GADD34) which promotes the dephosphorylation of eIF2a, leading to the recovery of protein translation after ESAT-6 stimulation. The 38 kDa antigen induces the production of ROS and the subsequent ERS via ERO1a which regulates Ca2þ fluxes through inositol 1,4,5-triphate receptor (IP3R) and Sarco-endoplasmic Reticulum Calcium Atpase (SERCA). ATF6 is released from Bip for trafficking to the Golgi apparatus where it is sequentially cleaved to a 50 kD active fragment including the N-terminal by site 1 and site 2 proteases at the transmembrane site. ATF6 then translocates to the nucleus to promote transcription of the ERSE-I, ERSE- II, UPR element (UPRE) and cAMP response element (CRE) genes. Unlike PERK and IRE1, nothing is known about the interaction between mycobacteria and the ATF6 pathway.
Please cite this article in press as: Cui Y, et al., The endoplasmic reticulum stress response: A link with tuberculosis?, Tuberculosis (2016), http:// dx.doi.org/10.1016/j.tube.2015.12.009
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in ER stress (ERS) which is also characterized by an expansion in the ER compartment [6e9]. The host cell responds with the unfolded protein response (UPR) which suspends the synthesis of new proteins and thereby reduces accumulation of unfolded/misfolded proteins in the ER to restore normal physiological function. Prolonged and uncontrolled ERS can lead to activation of a triad of signaling pathways moving the cell towards apoptosis. Here, we summarize recent advances in our understanding of the diversity of molecular mechanisms and signaling pathways that regulate ERS as related to Mtb infection. Throughout the review reference should be made to Figure 1. 2. The endoplasmic reticulum stress-associated triad of pathways 2.1. Chaperone involvement in UPR Glucose regulated protein (GRP78/Bip) is a member of heat shock protein 70 (Hsp70) family [8]. In addition to the ER, Bip is also found in mitochondria, the nucleus and has been found on the surface of tumor cells [9,10]. As a chaperone, Bip is expressed abundantly during stress conditions such as of glycopenia and low oxygen and Ca2þ and participates in protein folding and transportation. Some reports suggest that Bip is also upregulated by infection with Mtb and other mycobacterial spp [11e13]. Thus, Bip plays an important role in maintaining the steady state of the ER and protecting the cells from apoptosis. Under normal physiological conditions, inactive Bip binds noncovalently to the lumen domain of three kinds of transmembrane proteins. These are inositol-requiring kinase/endoribonuclease 1 (IRE1), protein kinase activated by double-stranded RNA (PKR)-like ER kinase (PERK) and activating transcription actor 6 (ATF6). The Mtb 38 kDa antigen is thought to increase the expression of MCP-1induced protein (MCPIP), a pro-inflammatory cytokine which increases the generation of ROS causing protein misfolding in the ER. This leads to the release of Bip from IRE1, PERK and ATF6 which is then able to bind unfolded-or misfolded proteins [14]. Bip has two major activities, namely (i) transferring misfolded proteins to the cytoplasm for 26s ubiquitination and degradation, and (ii) ATPmediated accelerated protein folding with transfer to the Golgi apparatus. After dissociation from Bip, IRE1, PERK and ATF6 activate the downstream UPR via different signaling pathways which finally returns the physiological function of the ER to normal. Bip then resumes its inactive state by binding to IRE1, PERK and ATF6s [15]. It is important to note that, some studies indicate that Mtb proteins such as ESAT6 or heparin-binding haemagglutinin antigen (HBHA) can induce UPR [12,13]. ESAT-6 is released into culture filtrates by Mtb after short periods of growth. HBHA is present on the bacterial cell surface and it can reach the culture filtrate. There were experiments showed that 1.5 107/ml Mtb carry 0.055 mg/ml ESAT6 [12,16], and 1 107/ml Mycobacterium smegmatis obtain 0.35e0.4 mg/ml recombinant HBHA protein which is similar to the native HBHA obtained from Mtb H37Ra [13,17]. Based on these experiments results, we can deduce that at least 1.0 106/ml of Mtb can lead to induction of UPR in macrophages. 2.2. The IRE1a pathway This branch of the ERS pathway is mediated by IRE1a, a type I transmembrane protein that consists of a N-terminal luminal sensor domain and a C-terminal cytosolic domain that is responsible for both kinase and RNase activities [18,19]. Upon ERS, the luminal domain of dissociated IRE1a forms homodimers in the ER membrane, while the cytosolic domain of IRE1a autophosphorylates to stimulate its kinase and RNase activities [20].
3
These activities initiate the translational frame shift that generates a 41 kDa CREB/ATF basic leucine zipper (bZiP)-containing transcription factor [21]. A potent transcription activator, XBP1 binds to the UPR element (UPRE) and to the ERS-response elements I and II (ERSE-I and ERSE-II) in the promoter regions of target genes, which induces the expression of a large number of other related genes to reduce or discontinue ERS and to restore ER homeostasis. Macrophages under ERS are reported to be hyper-responsive to XBPdependent TLR stimulation during Mtb infection and TLRs play important roles in initiating control of intracellular Mtb replication [11,22]. In addition to its cytoprotective function, IRE1a can also induce apoptosis [23]. Mtb and its antigens have been shown to be associated with IRE1a/TRAF2/ASK1 activation and to result in apoptosis [14,24]. The cytosolic RNase domain of phosphorylated IRE1a connects with TNF-receptor associated factor 2 (TRAF2) and subsequently forms a IRE1-TRAF2-ASK1complex with apoptosis signal regulating kinase 1 (ASK1), which activates the downstream Jun-Nterminal kinase (JNK) and mitogen-activated protein kinases (p38 MAPK) [25]. M. kansasii can trigger ERS-induced apoptosis by the IRE1a/ASK1/JNK cascade and the Mtb 38 kDa antigen can activate MAPK phosphorylation in both a TLR2-and TLR4-dependent manner [14,22]. The activated JNK can transfer from the cytoplasm to the nucleus to activate c-Jun, c-Fos, EIK-1 and other transcription factors through phosphorylation and to regulate the expression of the downstream related apoptosis target genes. Lim et al. [10] report that the 38 kDa antigen-induced C/EBP-homologous protein (CHOP) production is decreased when the JNK pathway is inhibited. In addition, JNK not only phosphorylates Bcl-2 to inhibit its anti-apoptotic activity, but can also phosphorylate Bax which translocates into mitochondria and activates Bak to promote apoptosis in A549 cells stimulated by ESAT-6 [24,26e28]. Inhibition of the p38 MAPK pathway reduces protein phosphatase activity, which activates JNK and significantly increases CHOP production during stimulation by the 38 kDa antigen [14]. Recently, regulated IRE1-dependent decay of mRNA (RIDD) has been shown to reduce ER localized mRNAs after Mtb infection [11]. This process can selectively target and degrade mRNAs encoding proteins involved in protein folding. Prolonged activation of RIDD signaling can promote cell death through a process shown to be dependent upon the conformational state of IRE1a [29,30]. IRE1a also excises microRNAs and regulates the expression of caspase. 2.3. The PERK pathway PERK is also a type I transmembrane protein with serine/threonine protein kinase activity. The structure and function of PERK and IRE1a are very similar, but the cytosolic domain of the former does not have endonuclease activity [31]. Recent evidence suggests that Mtb and its 38 kDa antigen can activate the PERK/eIF2a/CHOP pathway [11,14]. Upon ERS, the chaperone BiP is released from PERK which then undergoes oligomerization and trans-autophosphorylation. Activated PERK phosphorylates Ser51 of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) which inhibits GDP-GTP exchange in the translation initiation complexes eIF2-GTP-Met-tRNAMet which is required for the initiai tion phase of polypeptide chain synthesis. These processes in turn attenuate translation initiation to reduce the ER protein-folding load through the ERAD process [32]. Lee et al. [7] report that the phosphorylation of eIF2a is decreased at an early time point after Mtb infection, which is due to the loss of important functions that inhibit translation by Mtb in host cells. However, phosphorylated eIF2a selectively induces the expression of activating transcription factor 4 (ATF4) mRNA through the uORFs scanning ignored mechanism. ATF4 belongs to
Please cite this article in press as: Cui Y, et al., The endoplasmic reticulum stress response: A link with tuberculosis?, Tuberculosis (2016), http:// dx.doi.org/10.1016/j.tube.2015.12.009
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the cAMP response element binding protein (CREB) family and not only can induce transcription of some ER chaperone proteins and UPR-related transcription factor genes, which then enter the nucleus, but also transfers ATF6 from the ER to the Golgi apparatus. The study of Choi et al. [27] indicates that ESAT-6 induces the expression of CHOP via ATF4. CHOP is a member of C/EBP transcription factor family, containing an N-terminal transcription activation domain and a C-terminal bZIP domain [33]. Generally, CHOP is mainly located in the cytoplasm and the base line expression level is very low, whereas upon ERS, the level of expression increases with transfer to and aggregation in the nucleus [34]. Recent studies suggest that CHOP expression is increased in granulomas in response to mycobacterial infection [35]. If CHOP expression is suppressed experimentally, Mtb survival increases. Interestingly, live Mtb induces CHOP expression, but heat-killed Mtb does not. This may be related to the level of eIF2a phosphorylation. The inhibition of phosphorylation of eIF2a by live Mtb is thought to be a survival strategy of mycobacteria [24]. Choi et al. [9] have also reported that CHOP expression is also involved in HBHA-induced upregulation of IL-6 and MCP-1 production through the activation of NF-kB. Excessive expression of CHOP can promote cell apoptosis in several ways: (1) activation of DNA damageinducible transcript 34 (GADD34). GADD34 is a regulated subunit of the coding protein phosphorylase I complex and is found to increase gradually after ESAT-6 stimulation [24], and together with protein phosphatase 2c promotes the dephosphorylation of eIF2a, leading to the recovery of protein translation; (2) activation of death receptor 5 (DR5) by regulating the expression of TRAIL-R2, thereby activating the caspase protein cascade [36]; (3) activation of endoplasmic oxidoreductin 1(ERO1). The 38 kDa antigen induces the production of ROS and the subsequent ERS via ERO1a which transfers electrons from protein disulfide isomerase to O2 to form H2O2 leading to high concentrations of peroxide in the ER environment, which itself leads to apoptosis [14]; (4) activation of TRB3 and Bim [37,38]; (5) inhibition of Bcl-2. Choi et al. [12,24] report that ESAT-6 induces CHOP to form dimers with CREB, leading to decreased Bcl-2 expression and increased Bax expression. Although PERK, ATF6 and IRE1a can all induce the transcription of CHOP, PERK/eIF2a/ATF4 is the main signaling pathway of CHOP protein expression [39]. Therefore, PERK inhibits protein synthesis mainly through eIF2a and promotes early cell survival, and promotes apoptosis by activating the CHOP downstream during the prolonged ERS observed in mycobacterial infection. A recent research indicates that IRE1a is activated very early and spliced XBP1 accumulates very quickly, until the IRE1 endonuclease activity is attenuated at a relatively early time point. Whereas, ATF4 translation occurs at a slow rate and dephosphorylation of eIF2a occurs late in 50 h by imaging of single resistant cell responses to ER stress [40]. Thus, we conclude that the IRE1a pathway play a protective role in the early stages of TB infection and the PERK pathway plays an apoptotic role in the late stages of the laten TB infection. On one hand cell apoptosis can control effectively the spread of mycobacterial infection, on the other hand, induction of apoptosis by live Mtb through prevention of phosphorylation of eIF2a can also lead to the survival of mycobacteria [11,14]. 2.4. The ATF6 pathway ATF6 is a type II ER transmembrane protein which consists of a N-terminal located in the cytoplasm with a CREB/ATF bZIP transcription factor domain and a C-terminal located in the ER lumen with multiple structural domains. In mammalian cells, ATF6 generally includes two subtypes, ATF6a and ATF6b [41]. Upon ERS, ATF6 is released from Bip for trafficking to the Golgi apparatus where it is sequentially cleaved to a 50 kD active fragment
including the N-terminal by site 1 and site 2 proteases at the transmembrane site [42]. ATF6 then translocates to the nucleus to promote transcription of the ERSE-I, ERSE- II, UPR element (UPRE) and cAMP response element (CRE) genes. ATF6 not only regulates the expression of XBP1, but also bind directly with the XBP1 protein to promote the expression of UPR-related proteins. Finally, all the processes above attenuate the accumulation of unfolded or misfolded proteins which relieves the damage to the ER [43]. 2.5. Ca2þ, a crucial factor in endoplasmic reticulum stress The ER is a major reservoir of Ca2þ inside the cell. During Mtb infection CHOP promotes the release of Ca2þ from the ER through the inositol phosphate receptor IP3, which not only damages chaperone function and protein folding capacity, but also enables Ca2þ to enter the mitochondria resulting in oxidative stress which induces apoptosis [13,24]. Increases in Ca2þ concentrations resulting from Mtb infection are known to produce ROS resulting in apoptosis [18]. Ca2þcan also be transported back to the ER from the cytoplasm through the sarcoplasm/ER calcium ATPase (SERCA) in order to maintain the balance of intracellular Ca2þ. Calreticulin, a major Ca2þ-binding ER chaperone is also a key component for folding of newly synthesized proteins and for other quality control pathways of the ER. Calreticulin is a glycoprotein chaperone, over expression of which can lead to increased sensitivity to apoptosis [44]. Calpain, a Ca2þ activated neutral proteinase can induce caspase 12 expression during ESAT-6 stimulation which is known as a pore-forming cell membrane protein [24]. In addition, activated CHOP and JNK protein kinase can induce the changes in Bak and Bax conformation, which destroys the integrity of the membrane and releases the Ca2þ into the mitochondria resulting in the release of cytochrome C and leading to apoptosis during Mtb infection [14,24]. 2.6. Concluding remarks ER is not only the site of folding and transportation of proteins after synthesis, but also the major site of intracellular Ca2þ storage and synthesis of cholesterol steroids and lipids. Mycobacterial infection can induce ERS and damage the ER. In the early period, UPR is induced through three main signaling pathways, IRE1, PERK and ATF6 to suspend early protein synthesis thereby reducing the accumulation of unfolded- or misfolded proteins in the ER and restoring normal physiological cell function. In the late period, their respective pathways continue to activate the downstream apoptosis genes to promote cell death. On one hand cell apoptosis can control effectively the spread of mycobacterial infection, on the other hand, induction of apoptosis by live Mtb through prevention of phosphorylation of eIF2a can also lead to the survival of mycobacteria. Thus, apoptosis may not always be a good protective mechanism for the host. Unlike PERK and IRE1, nothing is known about the interaction between mycobacteria and the ATF6 pathway. TB remains a major cause of mortality in man control of which is hampered by drug resistance and multi-drug resistance. There clearly remains the potential of exploring these pathways as new avenues for therapy and prophylaxis through the induction of apoptosis in infected cells. Acknowledgments This work was supported by the MoSTRCUK international cooperation project (No. 2013DFG32500); National High Technology Research and Development Program of China (863 Program, No. 2012AA101302); Funding of State Key Lab of Agrobiotechnology
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(No. 2012SKLAB06-14); 2015 CAU Foreign Experts Major Projects (No: 2012z018) and High-end Foreign Experts Recruitment Program (No. GDW20151100036) Q4
Funding:
None.
Competing interests: Ethical approval:
None declared. Not required.
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Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW Q6
The endoplasmic reticulum stress response: A link with tuberculosis?
Q5,1
Yongyong Cui a, Deming Zhao a, Paul Barrow b, Xiangmei Zhou a, * a
Q2
The State Key Lab of Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National TSE Lab, College of Veterinary Medicine, China Agricultural University, Beijing 100193, PR China b School of Veterinary Medicine, University of Nottingham, Sutton Bonington, Loughborough, Leicestershire, Le12SRD, UK
a r t i c l e i n f o
s u m m a r y
Article history: Received 21 July 2015 Received in revised form 26 October 2015 Accepted 28 December 2015
Tuberculosis (TB) remains a major cause of mortality and morbidity in the worldwide. The endoplasmicreticulum stress (ERS) response constitutes a cellular process that is triggered by mycobacterial infection that disturbs the folding of proteins in the endoplasmic reticulum (ER). The unfolded protein response (UPR) is induced to suspend the synthesis of early proteins and reduce the accumulation of unfolded- or misfolded proteins in the ER restoring normal physiological cell function. Prolonged or uncontrolled ERS leads to the activation of three signaling pathways (IRE1, PERK and ATF6) which directs the cell towards apoptosis. The absence of this process facilitates spread of the mycobacteria within the body. We summarize here recent advances in understanding the signaling pathway diversity governing ERS in relation to TB. © 2015 Published by Elsevier Ltd.
Keywords: Tuberculosis Endoplasmic-reticulum stress (ERS) The unfolded protein response (UPR) Apoptosis Mycobacteria
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The endoplasmic reticulum stress-associated triad of pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Chaperone involvement in UPR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The IRE1a pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. The PERK pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. The ATF6 pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Ca2þ, a crucial factor in endoplasmic reticulum stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Q3
It is more than one hundred years since Mycobacterium tuberculosis (Mtb) was first characterized by Robert Koch. Tuberculosis (TB) remains one of the most serious global diseases affecting man,
* Corresponding author. Tel.: þ86 10 62734618; fax: þ86 10 62732975. E-mail addresses: [email protected] (Y. Cui), [email protected] (D. Zhao), [email protected] (P. Barrow), [email protected] (X. Zhou).
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preferentially affecting aged individuals or those affected by the human immunodeficiency virus (HIV). More than 9 million new cases were reported in 2013 with 1.5 million deaths in the world. Multi-drug resistance is a particularly intractable problem with an estimated 480,000 new cases and 210,000 deaths in 2013, of which 9.0% were reported in some countries to be infected with extensively drug resistant (XDR) strains [1]. Mtb is highly adapted to the human host and has multiple mechanisms to resist the host immune response after entry primarily through the respiratory tract. Failure of the immune
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response to clear infection results in death of individual cells. Interestingly, cell death is a double-edged sword in the competition between host and pathogen. Necrosis favors the spread of Mtb, whereas, by contrast, apoptosis facilitates controlling the infection [2]. Bacterial killing by infected cells is mediated by the production of cytokines and intracellular enzymes which also results in autophagy. Macrophages are the major host cell type infected by Mtb. In earlier studies, Mtb is considered to resident in phagosomal compartments which immediately fuse with lysosomes after entering into the cells. Phagolysosome fusion offers an acidic environment rich in hydrolytic enzymes that degrade and kill bacteria. Whereas, in recent studies, Mtb surprisingly translocate from phagolysosomes into the cytosol in nonapoptotic cells, but not for M. bovis BCG or in heat-killed mycobacteria due to the virulent strains secreting mycobacterial gene products the 10-kDa culture
filtrate protein (CFP-10) and the 6-kDa early secreted antigenic target (ESAT-6) which have cytolytic ability [3e5]. Cytosolic Mtb has been reported to induce type I Interferons (IFNs) and to activate autophage via the stimulator of interferon gene (STING) pathway [6]. As known, STING locates in the endoplasmic reticulum (ER) membrane. Infection of macrophages by the virulent H37Rv and attenuated H37Ra strains results in increases in the amount of rough- (RER) and smooth- (SER) endoplasmic reticulum respectively [7]. ER is not only the major site of folding and transportation of proteins after synthesis, but also the major storage site of intracellular Ca2þ and of synthesis of cholesterol steroids and many lipids. Mycobacterial infection results in loss of Ca2þ from the ER and an increase in the intracellular redox state which results in accumulation of unfolded or misfolded proteins in the ER resulting
Figure 1. Cellular responses to endoplasmic reticulum stress induced by mycobacteria. Under normal physiological conditions, inactive Bip binds to the lumen domain of three kinds of transmembrane protein: inositol-requiring kinase/endoribonuclease 1 (IRE1), protein kinase activated by double-stranded RNA (PKR)-like ER kinase (PERK) and activating transcription actor 6 (ATF6). The accumulation of unfolded or misfolded proteins in the ER resulting in ER stress (ERS) when the cells are infected by Mtb or antigen proteins like ESAT-6. The Bip from IRE1, PERK and ATF6 is then able to bind unfolded-or misfolded proteins. The luminal domain of dissociated IRE1a forms homodimers in the ER membrane, while the cytosolic domain of IRE1a auto-phosphorylates to stimulate the kinase and RNase activities and to splice XBP-1 mRNA which binds to the UPR element (UPRE) and to the ER stress-response elements I and II (ERSE-I and ERSE-II) in the promoter regions of target genes. IRE1 can also recruit TRAF2 and ASK1, leading to down-stream activation of JNK and p38 MAPK when the cells are infected by M. kansasii or the Mtb 38 kDa antigen, then activates CHOP and other apoptotic transcription factors. In addition, the Mtb 38 kDa antigen can activate MAPK phosphorylation in both a TLR2-and TLR4-dependent manner. Regulated IRE1-dependent decay of mRNA (RIDD) has been shown to reduce ER localized mRNAs after Mtb infection. Activated PERK undergoes oligomerization and trans-autophosphorylation when the cells are infected by Mtb or antigen proteins like ESAT-6. PERK phosphorylates Ser51 of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) which selectively induces the expression of activating transcription factor 4 (ATF4) mRNA which can induce transcription of some ER chaperone proteins and UPR-related transcription factor genes. CHOP can activate DNA damage-inducible transcript 34 (GADD34) which promotes the dephosphorylation of eIF2a, leading to the recovery of protein translation after ESAT-6 stimulation. The 38 kDa antigen induces the production of ROS and the subsequent ERS via ERO1a which regulates Ca2þ fluxes through inositol 1,4,5-triphate receptor (IP3R) and Sarco-endoplasmic Reticulum Calcium Atpase (SERCA). ATF6 is released from Bip for trafficking to the Golgi apparatus where it is sequentially cleaved to a 50 kD active fragment including the N-terminal by site 1 and site 2 proteases at the transmembrane site. ATF6 then translocates to the nucleus to promote transcription of the ERSE-I, ERSE- II, UPR element (UPRE) and cAMP response element (CRE) genes. Unlike PERK and IRE1, nothing is known about the interaction between mycobacteria and the ATF6 pathway.
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in ER stress (ERS) which is also characterized by an expansion in the ER compartment [6e9]. The host cell responds with the unfolded protein response (UPR) which suspends the synthesis of new proteins and thereby reduces accumulation of unfolded/misfolded proteins in the ER to restore normal physiological function. Prolonged and uncontrolled ERS can lead to activation of a triad of signaling pathways moving the cell towards apoptosis. Here, we summarize recent advances in our understanding of the diversity of molecular mechanisms and signaling pathways that regulate ERS as related to Mtb infection. Throughout the review reference should be made to Figure 1. 2. The endoplasmic reticulum stress-associated triad of pathways 2.1. Chaperone involvement in UPR Glucose regulated protein (GRP78/Bip) is a member of heat shock protein 70 (Hsp70) family [8]. In addition to the ER, Bip is also found in mitochondria, the nucleus and has been found on the surface of tumor cells [9,10]. As a chaperone, Bip is expressed abundantly during stress conditions such as of glycopenia and low oxygen and Ca2þ and participates in protein folding and transportation. Some reports suggest that Bip is also upregulated by infection with Mtb and other mycobacterial spp [11e13]. Thus, Bip plays an important role in maintaining the steady state of the ER and protecting the cells from apoptosis. Under normal physiological conditions, inactive Bip binds noncovalently to the lumen domain of three kinds of transmembrane proteins. These are inositol-requiring kinase/endoribonuclease 1 (IRE1), protein kinase activated by double-stranded RNA (PKR)-like ER kinase (PERK) and activating transcription actor 6 (ATF6). The Mtb 38 kDa antigen is thought to increase the expression of MCP-1induced protein (MCPIP), a pro-inflammatory cytokine which increases the generation of ROS causing protein misfolding in the ER. This leads to the release of Bip from IRE1, PERK and ATF6 which is then able to bind unfolded-or misfolded proteins [14]. Bip has two major activities, namely (i) transferring misfolded proteins to the cytoplasm for 26s ubiquitination and degradation, and (ii) ATPmediated accelerated protein folding with transfer to the Golgi apparatus. After dissociation from Bip, IRE1, PERK and ATF6 activate the downstream UPR via different signaling pathways which finally returns the physiological function of the ER to normal. Bip then resumes its inactive state by binding to IRE1, PERK and ATF6s [15]. It is important to note that, some studies indicate that Mtb proteins such as ESAT6 or heparin-binding haemagglutinin antigen (HBHA) can induce UPR [12,13]. ESAT-6 is released into culture filtrates by Mtb after short periods of growth. HBHA is present on the bacterial cell surface and it can reach the culture filtrate. There were experiments showed that 1.5 107/ml Mtb carry 0.055 mg/ml ESAT6 [12,16], and 1 107/ml Mycobacterium smegmatis obtain 0.35e0.4 mg/ml recombinant HBHA protein which is similar to the native HBHA obtained from Mtb H37Ra [13,17]. Based on these experiments results, we can deduce that at least 1.0 106/ml of Mtb can lead to induction of UPR in macrophages. 2.2. The IRE1a pathway This branch of the ERS pathway is mediated by IRE1a, a type I transmembrane protein that consists of a N-terminal luminal sensor domain and a C-terminal cytosolic domain that is responsible for both kinase and RNase activities [18,19]. Upon ERS, the luminal domain of dissociated IRE1a forms homodimers in the ER membrane, while the cytosolic domain of IRE1a autophosphorylates to stimulate its kinase and RNase activities [20].
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These activities initiate the translational frame shift that generates a 41 kDa CREB/ATF basic leucine zipper (bZiP)-containing transcription factor [21]. A potent transcription activator, XBP1 binds to the UPR element (UPRE) and to the ERS-response elements I and II (ERSE-I and ERSE-II) in the promoter regions of target genes, which induces the expression of a large number of other related genes to reduce or discontinue ERS and to restore ER homeostasis. Macrophages under ERS are reported to be hyper-responsive to XBPdependent TLR stimulation during Mtb infection and TLRs play important roles in initiating control of intracellular Mtb replication [11,22]. In addition to its cytoprotective function, IRE1a can also induce apoptosis [23]. Mtb and its antigens have been shown to be associated with IRE1a/TRAF2/ASK1 activation and to result in apoptosis [14,24]. The cytosolic RNase domain of phosphorylated IRE1a connects with TNF-receptor associated factor 2 (TRAF2) and subsequently forms a IRE1-TRAF2-ASK1complex with apoptosis signal regulating kinase 1 (ASK1), which activates the downstream Jun-Nterminal kinase (JNK) and mitogen-activated protein kinases (p38 MAPK) [25]. M. kansasii can trigger ERS-induced apoptosis by the IRE1a/ASK1/JNK cascade and the Mtb 38 kDa antigen can activate MAPK phosphorylation in both a TLR2-and TLR4-dependent manner [14,22]. The activated JNK can transfer from the cytoplasm to the nucleus to activate c-Jun, c-Fos, EIK-1 and other transcription factors through phosphorylation and to regulate the expression of the downstream related apoptosis target genes. Lim et al. [10] report that the 38 kDa antigen-induced C/EBP-homologous protein (CHOP) production is decreased when the JNK pathway is inhibited. In addition, JNK not only phosphorylates Bcl-2 to inhibit its anti-apoptotic activity, but can also phosphorylate Bax which translocates into mitochondria and activates Bak to promote apoptosis in A549 cells stimulated by ESAT-6 [24,26e28]. Inhibition of the p38 MAPK pathway reduces protein phosphatase activity, which activates JNK and significantly increases CHOP production during stimulation by the 38 kDa antigen [14]. Recently, regulated IRE1-dependent decay of mRNA (RIDD) has been shown to reduce ER localized mRNAs after Mtb infection [11]. This process can selectively target and degrade mRNAs encoding proteins involved in protein folding. Prolonged activation of RIDD signaling can promote cell death through a process shown to be dependent upon the conformational state of IRE1a [29,30]. IRE1a also excises microRNAs and regulates the expression of caspase. 2.3. The PERK pathway PERK is also a type I transmembrane protein with serine/threonine protein kinase activity. The structure and function of PERK and IRE1a are very similar, but the cytosolic domain of the former does not have endonuclease activity [31]. Recent evidence suggests that Mtb and its 38 kDa antigen can activate the PERK/eIF2a/CHOP pathway [11,14]. Upon ERS, the chaperone BiP is released from PERK which then undergoes oligomerization and trans-autophosphorylation. Activated PERK phosphorylates Ser51 of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) which inhibits GDP-GTP exchange in the translation initiation complexes eIF2-GTP-Met-tRNAMet which is required for the initiai tion phase of polypeptide chain synthesis. These processes in turn attenuate translation initiation to reduce the ER protein-folding load through the ERAD process [32]. Lee et al. [7] report that the phosphorylation of eIF2a is decreased at an early time point after Mtb infection, which is due to the loss of important functions that inhibit translation by Mtb in host cells. However, phosphorylated eIF2a selectively induces the expression of activating transcription factor 4 (ATF4) mRNA through the uORFs scanning ignored mechanism. ATF4 belongs to
Please cite this article in press as: Cui Y, et al., The endoplasmic reticulum stress response: A link with tuberculosis?, Tuberculosis (2016), http:// dx.doi.org/10.1016/j.tube.2015.12.009
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the cAMP response element binding protein (CREB) family and not only can induce transcription of some ER chaperone proteins and UPR-related transcription factor genes, which then enter the nucleus, but also transfers ATF6 from the ER to the Golgi apparatus. The study of Choi et al. [27] indicates that ESAT-6 induces the expression of CHOP via ATF4. CHOP is a member of C/EBP transcription factor family, containing an N-terminal transcription activation domain and a C-terminal bZIP domain [33]. Generally, CHOP is mainly located in the cytoplasm and the base line expression level is very low, whereas upon ERS, the level of expression increases with transfer to and aggregation in the nucleus [34]. Recent studies suggest that CHOP expression is increased in granulomas in response to mycobacterial infection [35]. If CHOP expression is suppressed experimentally, Mtb survival increases. Interestingly, live Mtb induces CHOP expression, but heat-killed Mtb does not. This may be related to the level of eIF2a phosphorylation. The inhibition of phosphorylation of eIF2a by live Mtb is thought to be a survival strategy of mycobacteria [24]. Choi et al. [9] have also reported that CHOP expression is also involved in HBHA-induced upregulation of IL-6 and MCP-1 production through the activation of NF-kB. Excessive expression of CHOP can promote cell apoptosis in several ways: (1) activation of DNA damageinducible transcript 34 (GADD34). GADD34 is a regulated subunit of the coding protein phosphorylase I complex and is found to increase gradually after ESAT-6 stimulation [24], and together with protein phosphatase 2c promotes the dephosphorylation of eIF2a, leading to the recovery of protein translation; (2) activation of death receptor 5 (DR5) by regulating the expression of TRAIL-R2, thereby activating the caspase protein cascade [36]; (3) activation of endoplasmic oxidoreductin 1(ERO1). The 38 kDa antigen induces the production of ROS and the subsequent ERS via ERO1a which transfers electrons from protein disulfide isomerase to O2 to form H2O2 leading to high concentrations of peroxide in the ER environment, which itself leads to apoptosis [14]; (4) activation of TRB3 and Bim [37,38]; (5) inhibition of Bcl-2. Choi et al. [12,24] report that ESAT-6 induces CHOP to form dimers with CREB, leading to decreased Bcl-2 expression and increased Bax expression. Although PERK, ATF6 and IRE1a can all induce the transcription of CHOP, PERK/eIF2a/ATF4 is the main signaling pathway of CHOP protein expression [39]. Therefore, PERK inhibits protein synthesis mainly through eIF2a and promotes early cell survival, and promotes apoptosis by activating the CHOP downstream during the prolonged ERS observed in mycobacterial infection. A recent research indicates that IRE1a is activated very early and spliced XBP1 accumulates very quickly, until the IRE1 endonuclease activity is attenuated at a relatively early time point. Whereas, ATF4 translation occurs at a slow rate and dephosphorylation of eIF2a occurs late in 50 h by imaging of single resistant cell responses to ER stress [40]. Thus, we conclude that the IRE1a pathway play a protective role in the early stages of TB infection and the PERK pathway plays an apoptotic role in the late stages of the laten TB infection. On one hand cell apoptosis can control effectively the spread of mycobacterial infection, on the other hand, induction of apoptosis by live Mtb through prevention of phosphorylation of eIF2a can also lead to the survival of mycobacteria [11,14]. 2.4. The ATF6 pathway ATF6 is a type II ER transmembrane protein which consists of a N-terminal located in the cytoplasm with a CREB/ATF bZIP transcription factor domain and a C-terminal located in the ER lumen with multiple structural domains. In mammalian cells, ATF6 generally includes two subtypes, ATF6a and ATF6b [41]. Upon ERS, ATF6 is released from Bip for trafficking to the Golgi apparatus where it is sequentially cleaved to a 50 kD active fragment
including the N-terminal by site 1 and site 2 proteases at the transmembrane site [42]. ATF6 then translocates to the nucleus to promote transcription of the ERSE-I, ERSE- II, UPR element (UPRE) and cAMP response element (CRE) genes. ATF6 not only regulates the expression of XBP1, but also bind directly with the XBP1 protein to promote the expression of UPR-related proteins. Finally, all the processes above attenuate the accumulation of unfolded or misfolded proteins which relieves the damage to the ER [43]. 2.5. Ca2þ, a crucial factor in endoplasmic reticulum stress The ER is a major reservoir of Ca2þ inside the cell. During Mtb infection CHOP promotes the release of Ca2þ from the ER through the inositol phosphate receptor IP3, which not only damages chaperone function and protein folding capacity, but also enables Ca2þ to enter the mitochondria resulting in oxidative stress which induces apoptosis [13,24]. Increases in Ca2þ concentrations resulting from Mtb infection are known to produce ROS resulting in apoptosis [18]. Ca2þcan also be transported back to the ER from the cytoplasm through the sarcoplasm/ER calcium ATPase (SERCA) in order to maintain the balance of intracellular Ca2þ. Calreticulin, a major Ca2þ-binding ER chaperone is also a key component for folding of newly synthesized proteins and for other quality control pathways of the ER. Calreticulin is a glycoprotein chaperone, over expression of which can lead to increased sensitivity to apoptosis [44]. Calpain, a Ca2þ activated neutral proteinase can induce caspase 12 expression during ESAT-6 stimulation which is known as a pore-forming cell membrane protein [24]. In addition, activated CHOP and JNK protein kinase can induce the changes in Bak and Bax conformation, which destroys the integrity of the membrane and releases the Ca2þ into the mitochondria resulting in the release of cytochrome C and leading to apoptosis during Mtb infection [14,24]. 2.6. Concluding remarks ER is not only the site of folding and transportation of proteins after synthesis, but also the major site of intracellular Ca2þ storage and synthesis of cholesterol steroids and lipids. Mycobacterial infection can induce ERS and damage the ER. In the early period, UPR is induced through three main signaling pathways, IRE1, PERK and ATF6 to suspend early protein synthesis thereby reducing the accumulation of unfolded- or misfolded proteins in the ER and restoring normal physiological cell function. In the late period, their respective pathways continue to activate the downstream apoptosis genes to promote cell death. On one hand cell apoptosis can control effectively the spread of mycobacterial infection, on the other hand, induction of apoptosis by live Mtb through prevention of phosphorylation of eIF2a can also lead to the survival of mycobacteria. Thus, apoptosis may not always be a good protective mechanism for the host. Unlike PERK and IRE1, nothing is known about the interaction between mycobacteria and the ATF6 pathway. TB remains a major cause of mortality in man control of which is hampered by drug resistance and multi-drug resistance. There clearly remains the potential of exploring these pathways as new avenues for therapy and prophylaxis through the induction of apoptosis in infected cells. Acknowledgments This work was supported by the MoSTRCUK international cooperation project (No. 2013DFG32500); National High Technology Research and Development Program of China (863 Program, No. 2012AA101302); Funding of State Key Lab of Agrobiotechnology
Please cite this article in press as: Cui Y, et al., The endoplasmic reticulum stress response: A link with tuberculosis?, Tuberculosis (2016), http:// dx.doi.org/10.1016/j.tube.2015.12.009
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(No. 2012SKLAB06-14); 2015 CAU Foreign Experts Major Projects (No: 2012z018) and High-end Foreign Experts Recruitment Program (No. GDW20151100036) Q4
Funding:
None.
Competing interests: Ethical approval:
None declared. Not required.
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