Host Translation at the Nexus of Infection and Immunity
2012; Cell Press; Volume: 12; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2012.09.006
ISSN1934-6069
Autores Tópico(s)Plant and Fungal Interactions Research
ResumoBy controlling gene expression at the level of mRNA translation, organisms temporally and spatially respond swiftly to an ever-changing array of environmental conditions. This capacity for rapid response is ideally suited for mobilizing host defenses and coordinating innate responses to infection. Not surprisingly, a growing list of pathogenic microbes target host mRNA translation for inhibition. Infection with bacteria, protozoa, viruses, and fungi has the capacity to interfere with ongoing host protein synthesis and thereby trigger and/or suppress powerful innate responses. This review discusses how diverse pathogens manipulate the host translation machinery and the impact of these interactions on infection biology and the immune response. By controlling gene expression at the level of mRNA translation, organisms temporally and spatially respond swiftly to an ever-changing array of environmental conditions. This capacity for rapid response is ideally suited for mobilizing host defenses and coordinating innate responses to infection. Not surprisingly, a growing list of pathogenic microbes target host mRNA translation for inhibition. Infection with bacteria, protozoa, viruses, and fungi has the capacity to interfere with ongoing host protein synthesis and thereby trigger and/or suppress powerful innate responses. This review discusses how diverse pathogens manipulate the host translation machinery and the impact of these interactions on infection biology and the immune response. A cardinal means by which microbes influence host physiology is through the cellular translation machinery. Indeed, microbes and their hosts strategically maneuver to control cellular messenger RNA (mRNA) translation for their own benefit, illustrating a spectrum of host-pathogen interactions. On one extreme, replication of obligate intracellular parasites like viruses is completely reliant on the host translational apparatus. Not only must viruses commandeer this machinery to translate their own mRNAs and ensure viral mRNAs compete with cellular counterparts, but they also thwart host defenses aimed at inactivating the cellular translation apparatus. Even bacteria and protozoa, which are not dependent upon host translational components for their protein synthetic needs, manipulate the cellular translation machinery. Pathogen-encoded effectors, like bacterial toxins, inhibit host translation. As virulence factors associated with severe infections, toxins kill eukaryotic cells and facilitate tissue invasion. While interfering with host mRNA translation limits production of host defenses, it can also generate a danger signal capable of triggering a conserved innate immune response. Sensing of pathogens indirectly by monitoring changes in cell homeostasis is used extensively by plants, where it is called effector-triggered immunity (Jones and Dangl, 2006Jones J.D.G. Dangl J.L. The plant immune system.Nature. 2006; 444: 323-329Crossref PubMed Scopus (2046) Google Scholar). Alternatively, changes in cellular protein synthesis can indicate host nutritional status and its relationship to a dynamic environment, illustrating how pathways that control mRNA translation are responsive to physiological stress and metabolic status. For persistent pathogens, monitoring of ongoing mRNA translation represents a vital window into the host metabolic state and prospects for future homeostasis. In addition, many cellular innate immune effectors are important regulators of global and mRNA specific translation. Finally, adaptive immunity requires presentation of protein antigens complexed with cell surface MHC molecules for immune surveillance. Thus, the cell protein repertoire can signal infection and is a key determinant discriminating self from nonself. In this review, we focus on how different pathogens induce changes to ongoing cellular protein synthesis and consider the varied strategies by which host translation impacts infection and immunity. Regulated mRNA translation is a powerful posttranscriptional means to control gene expression spatially and temporally in eukaryotes. In addition to fundamental roles in cell growth and proliferation, development, learning, memory, and synaptic plasticity, translational control plays a major role in host stress responses, including pathogenic infection, and defenses by enabling rapid responses in surroundings that abound with microbes. Indeed, the role of translation in infection and host immunity to viruses is aptly illustrated in crop plant species, where all known recessive resistance genes encode translation initiation factors (Truniger and Aranda, 2009Truniger V. Aranda M.A. Recessive resistance to plant viruses.Adv. Virus Res. 2009; 75: 119-159Crossref PubMed Google Scholar). With respect to infection and immune defenses, host translation is regulated primarily at the initiation and elongation steps (Figure 1). Before mRNA loading, the 40S ribosomal subunit forms a 43S complex with translation initiation factors and the methionine-charged initiator tRNA (Met-tRNAi; Figure 1). This requires eIF2, a heterotrimeric guanine nucleotide binding protein that in its active state forms a ternary complex (TC) containing GTP and the initiator tRNA, Met-tRNAi. The TC loads 40S ribosomes with Met-tRNAi and is required to initiate protein synthesis at open reading frames (ORFs) commencing with an AUG codon or near-cognate AUGs, with one exception described later (reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). Unlike the prokaryotic 30S ribosomal subunit that directly recognizes the Shine-Dalgarno RNA sequence upstream of the initiator AUG, eukaryotic 40S subunits require assistance from the heterotrimeric translation initiation factor eIF4F (reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). By binding to the 7-methylguanosine (m7G) cap structure that is present at the 5′ terminus of all nuclear transcribed eukaryotic mRNAs, eIF4F positions the ribosome onto the mRNA 5′ end and facilitates an ATP-dependent movement termed "scanning" that locates the 5′ proximal AUG on the majority of mRNAs (reviewed by Parsyan et al., 2011Parsyan A. Svitkin Y. Shahbazian D. Gkogkas C. Lasko P. Merrick W.C. Sonenberg N. mRNA helicases: the tacticians of translational control.Nat. Rev. Mol. Cell Biol. 2011; 12: 235-245Crossref PubMed Scopus (56) Google Scholar). eIF4F is comprised of the cap-binding protein eIF4E, the DEAD box RNA helicase eIF4A, and the large molecular scaffold eIF4G. While eIF4E binds the cap, eIF4G associates with ribosome-bound eIF3 to tether the 43S complex to the mRNA 5′ end. Once bound to eIF4G, eIF4E can be phosphorylated by an eIF4G-associated kinase, Mnk1 or Mnk2. Unlike Mnk2, which confers basal eIF4E phosphorylation, Mnk1 mediates inducible p38 and ERK-responsive eIF4E phosphorylation and links eIF4E phosphorylation to MAP kinase signaling. Finally, eIF4F assembly juxtaposes the mRNA polyadenylated 3′ end, bound by PABP, with the 5′ end through an interaction between eIF4G and PABP (reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). This probably limits 40S subunit recruitment to mRNAs containing intact 5′ and 3′ ends. Significantly, initiation is thought to be the rate-limiting step under most circumstances (reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). The extent to which translation of individual mRNAs varies with respect to eIF4F levels is heavily influenced by the degree of secondary structure in the 5′ untranslated region (UTR) (reviewed by Parsyan et al., 2011Parsyan A. Svitkin Y. Shahbazian D. Gkogkas C. Lasko P. Merrick W.C. Sonenberg N. mRNA helicases: the tacticians of translational control.Nat. Rev. Mol. Cell Biol. 2011; 12: 235-245Crossref PubMed Scopus (56) Google Scholar). Importantly, regulated binding of eIF4E to eIF4G represents a key point whereby physiological signals control initiation through assembly of a functional eIF4F complex (reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). This is mediated by the host ser/thr kinase mTOR complex 1 (mTORC1; Figure 2), which responds to changes in physiologic homeostasis, including growth factors, nutrients, amino acids, oxygen, and energy availability (reviewed by Laplante and Sabatini, 2012Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar) and controls activity of the eIF4E-binding protein family of translation repressors (4E-BP1,2,3). While hypophosphorylated 4E-BPs bind to eIF4E, prevent its assembly into the eIF4F complex, and suppress cap-dependent translation, hyperphosphorylation of 4E-BP by activated mTORC1 releases eIF4E, promotes eIF4E binding to eIF4G, and stimulates cap-dependent translation. Upon AUG recognition, GTP hydrolysis is stimulated by eIF5, an eIF2 GTPase-activating protein (GAP) that also stabilizes GDP binding to eIF2 and functions as a guanine nucleotide dissociation inhibitor (Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). While AUG recognition promotes inorganic phosphate release from eIF2, eIF5B-dependent 60S subunit joining promotes initiation factor release and allows inactive eIF2⋅GDP to access its heteropentameric subunit (α-ε) recycling factor, eIF2B, which exchanges eIF2-bound GDP for GTP (Figure 3; reviewed by Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). After AUG initiation codon recognition and 60S subunit joining, the 80S ribosome commences polypeptide chain elongation (Figure 1; reviewed in Dever and Green, 2012Dever T.E. Green R. The elongation, termination, and recycling phases of translation in eukaryotes.Cold Spring Harb. Perspect. Biol. 2012; 4: a013706Crossref Scopus (13) Google Scholar). This requires elongation factor eEF1A, a G protein that delivers aminoacylated tRNA to the ribosome and whose activity is regulated by the guanine nucleotide exchange factor (GEF) eEF1B, and eEF2, which promotes ribosome translocation after peptide bond formation. While casein kinase II and PKC stimulate eEF1A activity, eEF2 phosphorylation by eEF2 kinase inhibits elongation (Figure 2). Elongation continues until a termination codon is encountered. Microbial infection impacts host translation in a variety of ways. Not only can infection modify the translational capacity of the host, but regulated mRNA translation can influence microbial pathogenesis by limiting or promoting translation of host mRNAs encoding the effector proteins that mediate innate responses. Damage to epithelia by bacteria can suppress host translation via cell signaling pathways, alerting the host to danger. By introducing effectors directly into the cytoplasm, bacteria or protozoa can directly suppress host translation. Finally, viruses are absolutely dependent on the host translation machinery to produce their proteins, which are required for their replication, and must effectively seize control of translation factors and their extensive regulatory network. Some RNA viruses like poliovirus inactivate factors required for canonical cap-dependent translation of host mRNAs to favor noncanonical, cap-independent mechanisms that allow 40S ribosomes to be recruited to viral mRNA containing an internal ribosome entry site (IRES) (reviewed by Doudna and Sarnow, 2007Doudna J. Sarnow P. Translation initiation by viral internal ribosome entry sites.in: Mathews M. Sonenberg N. Hershey J.W.B. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2007: 129-153Google Scholar). DNA viruses produce capped and polyadenylated mRNAs similar to the host and must effectively recruit limiting translation components to viral mRNAs. For a more-detailed discussion of the varied tactics that viruses use to interact with the host to promote viral mRNA translation, the reader is referred to two recent reviews (Walsh and Mohr, 2011Walsh D. Mohr I. Viral subversion of the host protein synthesis machinery.Nat. Rev. Microbiol. 2011; 9: 860-875Crossref PubMed Scopus (36) Google Scholar; Walsh et al., 2012Walsh D. Mathews M. Mohr I. Tinkering with translation: Protein synthesis in virus-infected cells.in: Hershey J.W.B. Sonenberg N. Mathews M.B. Protein Synthesis and Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2012: 299-326Google Scholar). Their exquisite sensitivity to environmental factors, metabolic status, and stress coupled with their capacity to rapidly change host gene expression renders translation factors ideal innate immune effectors to directly limit pathogen replication. A seminal innate immune guardian is eIF2. Host translation initiation can be impaired by four cellular kinases that phosphorylate the α regulatory subunit of eIF2 on S51, each of which is triggered by a discrete environmental or metabolic stress (Figure 3). Double-strand RNA (dsRNA), a pathogen-associated molecular pattern (PAMP) indicative of virus infection, and the host protein PACT can each activate the dsRNA-dependent protein kinase PKR, an interferon (IFN)-induced eIF2α kinase that inhibits protein synthesis upon activation in virus-infected cells (Walsh et al., 2012Walsh D. Mathews M. Mohr I. Tinkering with translation: Protein synthesis in virus-infected cells.in: Hershey J.W.B. Sonenberg N. Mathews M.B. Protein Synthesis and Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2012: 299-326Google Scholar). In this manner, IFN production by infected cells induces the accumulation of antiviral host defense molecules in uninfected neighboring cells to restrict viral replication and spread (Walsh et al., 2012Walsh D. Mathews M. Mohr I. Tinkering with translation: Protein synthesis in virus-infected cells.in: Hershey J.W.B. Sonenberg N. Mathews M.B. Protein Synthesis and Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2012: 299-326Google Scholar). Exceeding the ER protein folding capacity engenders activation of PERK, an ER membrane spanning protein with a luminal sensor domain and a cytoplasmic eIF2α kinase domain (Ron and Walter, 2007Ron D. Walter P. Signal integration in the endoplasmic reticulum unfolded protein response.Nat. Rev. Mol. Cell Biol. 2007; 8: 519-529Crossref PubMed Scopus (1714) Google Scholar). Heme depletion, arsenite-induced oxidative stress, heat shock, and osmotic stress activate the eIF2α kinase HRI, while amino acid deprivation or UV light activates GCN2 (Lu et al., 2001Lu L. Han A.-P. Chen J.-J. Translation initiation control by heme-regulated eukaryotic initiation factor 2α kinase in erythroid cells under cytoplasmic stresses.Mol. Cell. Biol. 2001; 21: 7971-7980Crossref PubMed Scopus (119) Google Scholar; Deng et al., 2002Deng J. Harding H.P. Raught B. Gingras A.C. Berlanga J.J. Scheuner D. Kaufman R.J. Ron D. Sonenberg N. Activation of GCN2 in UV-irradiated cells inhibits translation.Curr. Biol. 2002; 12: 1279-1286Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Relative to its unphosphorylated form, eIF2 containing a phosphorylated α subunit exhibits greater affinity for the recycling factor eIF2B and inhibits its guanine nucleotide exchange factor (GEF) activity. Importantly, since eIF2B is limiting, small changes in phosphorylated eIF2α concentration have dramatic effects on translation initiation (Hinnebusch and Lorsch, 2012Hinnebusch A.G. Lorsch J.R. The Mechanism of Eukaryotic Translation Initiation: New Insights and Challenges.Cold Spring Harb. Perspect. Biol. 2012; (Published online July 18, 2012)https://doi.org/10.1101/cshperspect.a011544Crossref PubMed Scopus (21) Google Scholar). The consequences for viruses can be dire unless they have a strategy to prevent accumulation of phosphorylated eIF2, which can also result in autophagy (Tallóczy et al., 2002Tallóczy Z. Jiang W. Virgin 4th, H.W. Leib D.A. Scheuner D. Kaufman R.J. Eskelinen E.L. Levine B. Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway.Proc. Natl. Acad. Sci. USA. 2002; 99: 190-195Crossref PubMed Scopus (317) Google Scholar). Indeed, the ability to antagonize PKR, either via virus-encoded dsRNA decoy molecules, dsRNA-binding proteins, or PKR-binding proteins, each of which prevent PKR activation, or via induction of cellular PKR antagonists, represents a major strategy used by viruses (Table 1) to resist the potent antiviral effects of IFN (Walsh and Mohr, 2011Walsh D. Mohr I. Viral subversion of the host protein synthesis machinery.Nat. Rev. Microbiol. 2011; 9: 860-875Crossref PubMed Scopus (36) Google Scholar). Among the least sensitive to IFNs, large DNA viruses including adenoviruses (Ad), poxviruses, and herpesviruses encode multiple, independent effectors to prevent eIF2 phosphorylation, some of which are specific antagonists of different eIF2α kinases or globally suppress eIF2α phosphorylation (reviewed in Walsh et al., 2012Walsh D. Mathews M. Mohr I. Tinkering with translation: Protein synthesis in virus-infected cells.in: Hershey J.W.B. Sonenberg N. Mathews M.B. Protein Synthesis and Translational Control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York2012: 299-326Google Scholar). This latter class of effectors, including virus-encoded eIF2α pseudosubstrates and phosphatase regulatory components, potentially counteract PERK and GCN2, both of which also have antiviral activity (reviewed in Walsh and Mohr, 2011Walsh D. Mohr I. Viral subversion of the host protein synthesis machinery.Nat. Rev. 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Struct. Mol. Biol. 2009; 16: 63-70Crossref PubMed Scopus (29) Google Scholar), illustrating how viruses and their hosts continuously maneuver to control eIF2. Recently, eIF2α phosphorylation has been reported after infection with Listeria monocytogenes, Chlamydia trachomatis, or Yersinia pseudotuberculosis, all intracellular bacteria (Shrestha et al., 2012Shrestha N. Bahnan W. Wiley D.J. Barber G. Fields K.A. Schesser K. Eukaryotic initiation factor 2 (eIF2) signaling regulates proinflammatory cytokine expression and bacterial invasion.J. Biol. Chem. 2012; 287: 28738-28744Crossref PubMed Scopus (4) Google Scholar). Cells unable to phosphorylate eIF2α were more susceptible to bacterial invasion, illustrating a role for eIF2α phosphorylation in activating NF-κB and proinflammatory cytokine production. In the case of Yersinia, the bacterial YopJ protein impairs eIF2α phosphorylation by an unknown mechanism, hinting that bacteria and viruses both counteract host defenses that operate through eIF2 (Shrestha et al., 2012Shrestha N. Bahnan W. Wiley D.J. Barber G. Fields K.A. Schesser K. Eukaryotic initiation factor 2 (eIF2) signaling regulates proinflammatory cytokine expression and bacterial invasion.J. Biol. Chem. 2012; 287: 28738-28744Crossref PubMed Scopus (4) Google Scholar).Table 1Viral Strategies to Prevent or Counteract eIF2α PhosphorylationMechanismVirus (Gene Product)dsRNA BPsInfluenza (NS1), reovirus (σ3), HSV (Us11), HCMV (TRS1, IRS1), MCMV (m142, m143), EBV (SM), Vaccinia (E3L)RNA antagonists of PKRAdenovirus (VA RNA), HCV (IRES), EBV (EBERs)Protein antagonists of PKRSendai (C), HCV (NS5A), Adenovirus (E1b 55k, E4 orf6), KSHV (vIRF2), PRV (IE 180)PERK antagonistsHCV (E2), Influenza, TEV, TMV (activate host p58IPK), HSV1 (gB)eIF2α kinase pseudosubstrateVaccinia (K3L), Ranavirus (vIF2)eIF2α phosphatase regulatory subunitHSV (γ34.5), ASFV (DP71L), HPV (E6)eIF2-independent initiationCrPV, Sindbis virus, poliovirusTEV, tobacco etch virus; TMV, tobacco mosaic virus; ASFV, African swine fever virus; PRV, pseudorabies virus; MCMV, murine cytomegalovirus. Open table in a new tab TEV, tobacco etch virus; TMV, tobacco mosaic virus; ASFV, African swine fever virus; PRV, pseudorabies virus; MCMV, murine cytomegalovirus. Not all viruses prevent eIF2α phosphorylation. While many RNA viruses like vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) are exquisitely IFN sensitive, others use uncommon, alternative translation initiation strategies that do not require eIF2-mediated Met-tRNAi loading. Insect viruses like cricket paralysis virus (CrPV) and Plautia stali intestine virus represent the most extreme examples and contain an IRES that directly recruits 40S subunits without needing any initiation factors, bypassing tRNAi loading altogether (Wilson et al., 2000Wilson J.E. Pestova T.V. Hellen C.U. Sarnow P. Initiation of protein synthesis from the A site of the ribosome.Cell. 2000; 102: 511-520Abstract Full Text Full Text PDF PubMed Google Scholar; Spahn et al., 2004Spahn C.M. Jan E. Mulder A. Grassucci R.A. Sarnow P. 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While the hepatitis C virus (HCV) IRES also initiates translation in an eIF2-independent manner, elegant studies with an in vitro reconstituted system showed that eIF2D is required to recruit Met-tRNAi to 40S-mRNA complexes, whereas studies in cultured cells implicated a different eIF2-independent factor called eIF2A (Dmitriev et al., 2010Dmitriev S.E. Terenin I.M. Andreev D.E. Ivanov P.A. Dunaevsky J.E. Merrick W.C. Shatsky I.N. GTP-independent tRNA delivery to the ribosomal P-site by a novel eukaryotic translation factor.J. Biol. Chem. 2010; 285: 26779-26787Crossref PubMed Scopus (22) Google Scholar; Skabkin et al., 2010Skabkin M.A. Skabkina O.V. Dhote V. Komar A.A. Hellen C.U. Pestova T.V. Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling.Genes Dev. 2010; 24: 1787-1801Crossref PubMed Scopus (30) Google Scholar, Kim et al., 2011Kim S. Lee S. Shin J. Kim Y. Evnouchidou I. Kim D. Kim Y.K. Kim Y.E. Ahn J.H. Riddell S.R. et al.Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1.Nat. Immunol. 2011; 12: 984-991Crossref PubMed Scopus (28) Google Scholar). In some cases, chronic pathogen infection engenders persistent, unresolved ER stress. Exposure of cells to LPS, a PAMP produced by gram-negative bacteria that activates TLR4 signaling, stimulates proinflammatory cytokine and antimicrobial protein production causing ER stress (Woo et al., 2009Woo C.W. Cui D. Arellano J. Dorweiler B. Harding H. Fitzgerald K.A. Ron D. Tabas I. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling.Nat. Cell Biol. 2009; 11: 1473-1480Crossref PubMed Scopus (89) Google Scholar). PERK, which is activated by ER stress and phosphorylates eIF2α, suppresses global translation but promotes the translation of a subset of cellular mRNAs harboring upstream ORFs (uORFs). This mechanism is based on the property of eukaryotic ribosomes to infrequently reinitiate translation and on the time they transit through the 5′ UTR to reacquire an active TC before encountering the next AUG (Hinnebusch, 2011Hinnebusch A.G. Molecular mechanism of scanning and start codon selection in eukaryotes.Microbiol. Mol. Biol. Rev. 2011; 75: 434-467Crossref PubMed Scopus (46) Google Scholar). One such uORF-containing mRNA encodes the transcription factor ATF4, which in turn induces the transcription factors ATF-3 and CHOP (C/EBP homologous protein). While transient CHOP induction has a salubrious effect on cells, sustained production is harmful and causes apoptosis. During ER stress, macrophage TLR4 signaling stimulates eIF2B GEF activity, which enables continued synthesis of essential proteins without activating ATF4 and CHOP (Woo et al., 2012Woo C.W. Kutzler L. Kimball S.R. Tabas I. Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B.Nat. Cell Biol. 2012; 14: 192-200Crossref PubMed Scopus (17) Google Scholar). Similarly, activation of ER stress pathways may also be important for Mycobacterium tuberculosis survival in macrophages (Seimon et al., 2010Seimon T.A. Kim M.J. Blumenthal A. Koo J. Ehrt S. Wainwright H. Bekker L.G. Kaplan G. Nathan C. Tabas I. Russell D.G. Induction of ER stress in macrophages of tuberculosis granulomas.PLoS ONE. 2010; 5: e12772Crossref PubMed Scopus (22) Google Scholar; Lim et al., 2011Lim Y.J. Choi J.A. Choi H.H. Cho S.N. Kim H.J. Jo E.K. Park J.K. Song C.H. Endoplasmic reticulum stress pathway-mediated apoptosis in macrophages contributes to the survival of Mycobacterium tuberculosis.PLoS ONE. 2011; 6: e28531Crossref PubMed Scopus (5) Google Scholar). In contrast, sustained eIF2α phosphorylation can have severe pathogenic consequences. Bacterial components including LPS, cytolysins, and intracellular-acting toxins all induce ER stress (Zhang et al.,
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