Heptose 1,7-Bisphosphate Directed TIFA Oligomerization: A Novel PAMP-Recognizing Signaling Platform in the Control of Bacterial Infections
2018; Elsevier BV; Volume: 154; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2018.01.009
ISSN1528-0012
AutoresSuneesh Kumar Pachathundikandi, Steffen Backert,
Tópico(s)Aquaculture disease management and microbiota
ResumoThe mucosal epithelium of the gastrointestinal tract in mammals represents a highly complex system and the first protective barrier to the external environment, in which multiple dynamic physiologic processes are effectively coordinated. Every day, millions of food molecules are exchanged at this surface, one of the basic functions of the gastrointestinal tract. This organ is also the entry point for many different microbes from the environment, of which some are just passengers, some others can colonize at the epithelial surfaces, and a few open the epithelium for entry into the lamina propria and may cause severe infections. It has been well-established that microbial infection leads to inflammation and the recruitment of active immune cells at the sites of colonization to resolve the infection. Various studies reported increasing evidence on the role of epithelial cells as an innate immune platform for sensing different microbes and generating signals to control the infection.1Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb Symp Quant Biol. 1989; 54: 1-13Crossref PubMed Google Scholar, 2Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (664) Google Scholar, 3Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (2007) Google Scholar Detection of pathogen-associated molecular patterns (PAMPs), comprising flagellin, lipopolysaccharide (LPS), peptidoglycan, nucleic acids, and others, by the host initiates an innate immune reaction, which is important for pathogen defense and engagement of adaptive immunity. Several pattern recognition receptors, which detect these PAMPs, were identified through the research of almost 3 decades1Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb Symp Quant Biol. 1989; 54: 1-13Crossref PubMed Google Scholar and include the Toll-like receptors (TLRs), Nod-like receptors (NLRs), c-type lectin receptors, and RIG-1 like receptors.2Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (664) Google Scholar, 3Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (2007) Google Scholar Initially discovered by pioneering work in the group of Scott Gray-Owen,4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar it was very recently shown by several laboratories in a series of elegant studies that mammalian cells can also detect and respond to the bacterial sugar heptose-1,7-bisphosphate (HBP).5Gaudet R.G. Guo C.X. Molinaro R. et al.Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway.Cell Rep. 2017; 19: 1418-1430Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar, 7Stein S.C. Faber E. Bats S.H. et al.Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.PLoS Pathog. 2017; 13: e1006514Crossref PubMed Scopus (77) Google Scholar, 8Gall A. Gaudet R.G. Gray-Owen S.D. et al.TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection.mBio. 2017; 8 (e01168–17)Crossref Scopus (80) Google Scholar, 9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar HBP is a metabolic intermediate of LPS biosynthesis and highly conserved in Gram-negative bacteria, while being fully absent in mammals.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar The recognition of translocated HBP into the host cytosol activates a novel signaling cascade involving alpha-kinase 1 (ALPK1) and the phosphorylation-dependent oligomerization of the tumor necrosis factor (TNF-α) receptor–associated factor (TRAF)–interacting protein with the forkhead-associated domain (TIFA). It seems that this signaling induces the proinflammatory transcription factor nuclear factor (NF)-κB and innate and adaptive immune responses in vivo. Thus, HBP is a novel PAMP that triggers TIFA-dependent immunity to invasive and extracellular Gram-negative pathogens including Shigella flexneri, Salmonella enterica serovar Typhimurium, Neisseria meningitidis, and Helicobacter pylori.5Gaudet R.G. Guo C.X. Molinaro R. et al.Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway.Cell Rep. 2017; 19: 1418-1430Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar, 7Stein S.C. Faber E. Bats S.H. et al.Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.PLoS Pathog. 2017; 13: e1006514Crossref PubMed Scopus (77) Google Scholar, 8Gall A. Gaudet R.G. Gray-Owen S.D. et al.TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection.mBio. 2017; 8 (e01168–17)Crossref Scopus (80) Google Scholar, 9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Because the delivery of HBP into the host cell is required, this may represent an elegant mechanism by which the extracellular microbiota is not recognized. Here, we highlight this intriguing novel signaling cascade and discuss its importance in innate immunity and other host cell responses. The LPS of Gram-negative bacteria is a well-known PAMP recognized by TLR4. LPS consists of a hydrophobic lipid section, lipid-A, core oligosaccharide region, and outer polysaccharide region, the O-antigen (Figure 1A). The lipid-A of LPS is the only known inflammatory component and is detected by TLR4.2Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (664) Google Scholar Until recently, the core oligosaccharide region was not attributed for any inflammatory activity. However, the discovery of TIFA activation by HBP indicates that the metabolic precursors of the core oligosaccharide region are also detected by the mammalian host. The correct synthesis of LPS provides structural integrity to the bacterial outer membrane and protection from environmental challenges. Bacterial mutants defective in HBP synthesis produce a phenotype called "deep rough" owing to the deformed characteristic of the outer membrane and are more prone to external attack.10Raetz C.R. Whitfield C. Lipopolysaccharide endotoxins.Annu Rev Biochem. 2002; 71: 635-700Crossref PubMed Scopus (3356) Google Scholar The HBP biosynthetic pathway is thus an integral part of bacterial survival and natural selection (Figure 1B and C). This conserved and important determinant of fitness makes it a suitable PAMP for the innate immune detection by its host. The synthesis of heptose intermediates in bacteria is well-documented in the literature and genes involved in this pathway are widely conserved in Gram-negative bacteria. The biosynthesis of HBP is initiated in the nonoxidative phase of the pentose phosphate pathway, where the D-ribulose-5-phosphate produced in the oxidative phase is converted to either D-ribose-5-phosphate or D-xylulose-5-phosphate by phosphopentose isomerase RpiA and epimerase Rpe, respectively. The transketolase Tkt then transfers a 2-carbon portion of xylulose to a ribose molecule to form D-sedoheptulose-7-phosphate and glyceraldehyde-3-phosphate. Another isomerase enzyme, GmhA of the ADP-heptose pathway, converts D-sedoheptulose-7-phosphate to D-glycero-β-D-manno-heptose-7-phosphate (D-α, β-D-heptose-7-phosphate; Figure 1B). Next, HldE kinase activity transfers a phosphate group to form D-glycero-β-D-manno-heptose-1,7-phosphate or HBP. HBP production is present only in Gram-negative bacteria, but absent in other bacteria and eukaryotic cells. After HBP production, 3 sequential enzymes—GmhB, HldE, and HldD—convert HBP to ADP-L-glycero-β-D-manno-heptose, which forms the precursor for the inner LPS core.11Kneidinger B. Graninger M. Puchberger M. et al.Biosynthesis of nucleotide-activated D-glycero-D-manno-heptose.J Biol Chem. 2001; 276: 20935-20944Crossref PubMed Scopus (85) Google Scholar, 12Kneidinger B. Marolda C. Graninger M. et al.Biosynthesis pathway of ADP-L-glycero-beta-D-manno-heptose in Escherichia coli.J Bacteriol. 2002; 184: 363-369Crossref PubMed Scopus (147) Google Scholar Recent studies have identified HBP as a PAMP detected by TIFA in the cytoplasm of mammalian cells to stimulate innate and, subsequently, adaptive immune responses (model in Figure 2A). The detection of HBP in the cytoplasm requires the entry of this molecule into the cells. Initial studies showed that HBP, which is abundantly liberated by pathogenic and commensal Neisseria spp, potently activates NF-κB.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar In addition, transfected soluble lysates from other Gram-negative bacteria, Escherichia coli, S enterica, Burkholderia multivorans, and Haemophilus influenzae, but not Moraxella catarrhalis (which lacks the ADP-heptose pathway) activated NF-κB. Transfected soluble lysates from mutant E coli and N meningitidis strains disrupted in the upstream genes of HBP synthesis decreased NF-κB activity, but downstream pathway disruption had an enhancing effect, which suggests that HBP accumulation intensified the response.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar It has been shown that treating the cells with N meningitidis lysate alone activated TIFA, but HBP can also be released by growing bacteria, which represents an active route for this extracellular bacterium.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar, 6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar Further studies using S flexneri, an invasive enteropathogen, confirmed that HBP released during bacterial replication inside the cytoplasm augmented the TIFA surveillance to sense intracellular bacterial growth. TIFA deficiency abrogated the ability to differentiate logarithmic and stationary phases of intracellular bacterial growth. However, Salmonella grown in vacuoles is not sensed by TIFA, but a sifA gene mutant, which escaped the vacuole, significantly increased TIFA-mediated NF-κB activation.5Gaudet R.G. Guo C.X. Molinaro R. et al.Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway.Cell Rep. 2017; 19: 1418-1430Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Moreover, it is evident that HBP from bacteria is delivered through endocytosis or phagocytosis-mediated destruction.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar, 6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar Remarkably, S flexneri infection of intestinal epithelial cells showed that TIFA-mediated NF-κB activation in noninfected adjacent bystander cells through cell–cell communication.6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar Interestingly, the gastric pathogen H pylori uses a type IV secretion system (T4SS) for HBP delivery into the cytoplasm, which is apparently sensed by TIFA for NF-κB activation.7Stein S.C. Faber E. Bats S.H. et al.Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.PLoS Pathog. 2017; 13: e1006514Crossref PubMed Scopus (77) Google Scholar, 8Gall A. Gaudet R.G. Gray-Owen S.D. et al.TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection.mBio. 2017; 8 (e01168–17)Crossref Scopus (80) Google Scholar, 9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Bacteria may use any one of the above processes for delivering HBP into the host cell cytoplasm (Figure 2A). TIFA was initially identified as a TRAF2 or TRAF6 interacting protein in yeast and mammalian 2-hybrid screens. In addition, it was also reported that TIFA overexpression increased NF-κB and AP-1 transcriptional activities.13Kanamori M. Suzuki H. Saito R. et al.T2BP, a novel TRAF2 binding protein, can activate NF-kappaB and AP-1 without TNF stimulation.Biochem Biophys Res Commun. 2002; 290: 1108-1113Crossref PubMed Scopus (49) Google Scholar, 14Takatsuna H. Kato H. Gohda J. et al.Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling.J Biol Chem. 2003; 278: 12144-12150Crossref PubMed Scopus (71) Google Scholar Another study exhibited the molecular events of TIFA oligomerization and polyubiquitination of TRAF6, leading to the activation of inhibitor-κB kinase15Ea C.K. Sun L. Inoue J. et al.TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6.Proc Natl Acad Sci U S A. 2004; 101: 15318-15323Crossref PubMed Scopus (103) Google Scholar and this TIFA oligomer signaling platform consists of TRAFs and other interacting partners such as TAB2 (transforming growth factor β-activated kinase 1 [TAK1]-binding protein 2) and so on which was recently coined the "TIFAsome" (Figure 2A).4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar The discovery of HBP sensing by TIFA and activation of NF-κB intensified further research in this field to understand the mode of activation in response to different bacterial infections. TIFA possesses a forkhead-associated (FHA) domain, which specifically binds phospho-threonine and phospho-serine residues in proteins to exert its function. Intrinsically, TIFA forms dimers and phosphorylation at threonine residue 9 (Thr-9) in the N-terminus directs self-association to form TIFAsomes and activates NF-κB.9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 16Huang C.C. Weng J.H. Wei T.Y. et al.Intermolecular binding between TIFA-FHA and TIFA-pT mediates tumor necrosis factor alpha stimulation and NF-κB activation.Mol Cell Biol. 2012; 32: 2664-2673Crossref PubMed Scopus (33) Google Scholar Recent structural studies of TIFA proposed an antiparallel pair of head-to-tail binding between phospho-Thr-9 and the FHA domain, which allows exposure of the C-terminal region for TRAF6 binding.17Weng J.H. Hsieh Y.C. Huang C.C. et al.Uncovering the mechanism of forkhead-associated domain-mediated TIFA oligomerization that plays a central role in immune responses.Biochemistry. 2015; 54: 6219-6229Crossref PubMed Scopus (22) Google Scholar The Gram-negative bacterial metabolite HBP was later found to induce TIFA Thr-9 phosphorylation and the subsequent induction of proinflammatory gene expression.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar Further studies showed that HBP detection and TIFA activation occurs in the cytoplasm during the bacterial logarithmic growth phase and was found to be reduced at the stationary phase of intracellular S flexneri. Intact extracellular noninvasive S flexneri or extracellular stimulation with soluble bacterial lysate or cell free culture supernatants were unable to activate TIFAsome formation and further signaling.5Gaudet R.G. Guo C.X. Molinaro R. et al.Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway.Cell Rep. 2017; 19: 1418-1430Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Thus, TIFA seems to work as a part of a detector system that measures cytosolic bacterial growth through HBP sensing, but the exact binding partner is not identified so far. However, this ability can obviously differentiate invasive pathogenic bacteria, which breach the epithelial barrier, from the unwarranted detection of extracellular commensal gut microbiome that regulate homeostasis of the gut through symbiotic growth.18Wells J.M. Brummer R.J. Derrien M. et al.Homeostasis of the gut barrier and potential biomarkers.Am J Physiol Gastrointest Liver Physiol. 2017; 312: G171-G193Crossref PubMed Scopus (295) Google Scholar Therefore, it can be proposed that the microbiota is unable to deliver HBP, which protects the host from TIFAsome activation and bacterial clearance by the optimal innate immune responses (Figure 2B). Innate immune pathways, transmitted through Toll/interleukin (IL)-1 receptor (IL-1R), TNF receptor, and Nod, converge on activation of the proinflammatory transcription factor NF-κB. The TIFA pathway forms another wing of this innate immune mechanism and detects cytosolic growth of pathogenic bacteria. Three pathways, including TIFA, Toll/IL-1R, and TNF receptor , merge at the level of TRAF2/6 ubiquitin ligase oligomerization to activate NF-κB. Moreover, TIFA and Toll/IL-1R pathways proceed to the level of phosphorylation of TAK1 and NF-κB p65 nuclear translocation (Figure 2A). S flexneri, S enterica, and N meningitidis infection-mediated TIFAsome formation was also dependent on Thr-9 phosphorylation. In addition, FHA domain mutation (RKN mutant) and E178A mutant prevented TIFA–TRAF6 binding and further signaling.16Huang C.C. Weng J.H. Wei T.Y. et al.Intermolecular binding between TIFA-FHA and TIFA-pT mediates tumor necrosis factor alpha stimulation and NF-κB activation.Mol Cell Biol. 2012; 32: 2664-2673Crossref PubMed Scopus (33) Google Scholar Moreover, ALPK1 was found to be the mediator kinase or master regulator of TIFA-induced innate immune signaling in these bacterial infections.6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar TIFA deficiency or HBP mutants of H pylori almost completely abrogated NF-κB–mediated IL-8 production in infected epithelial cells. One major variation in ALPK1-mediated TIFAsome formation in H pylori infection was the presence of TRAF2 instead of TRAF6 in the interactome complex.7Stein S.C. Faber E. Bats S.H. et al.Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.PLoS Pathog. 2017; 13: e1006514Crossref PubMed Scopus (77) Google Scholar, 9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar In addition, it was reported that HBP is transferred into the cytoplasm through the T4SS of H pylori. Effector protein CagA,19Mueller D. Tegtmeyer N. Brandt S. et al.c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains.J Clin Invest. 2012; 122: 1553-1566Crossref PubMed Scopus (173) Google Scholar DNA,20Varga M.G. Shaffer C.L. Sierra J.C. et al.Pathogenic H. pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system.Oncogene. 2016; 35: 6262-6269Crossref PubMed Scopus (70) Google Scholar and peptidoglycan21Viala J. Chaput C. Boneca I.G. et al.Nod1 responds to peptidoglycan delivered by the H. pylori cag pathogenicity island.Nat Immunol. 2004; 5: 1166-1174Crossref PubMed Scopus (988) Google Scholar are other reported T4SS substrates; however, most of the NF-κB–mediated IL-8 secretion in epithelial cells was dependent on TIFAsome formation.8Gall A. Gaudet R.G. Gray-Owen S.D. et al.TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection.mBio. 2017; 8 (e01168–17)Crossref Scopus (80) Google Scholar In conclusion, the presence of microbial LPS synthesis intermediate molecule HBP in the cytoplasm of host cells was found to activate a novel innate immune pathway in various Gram-negative bacterial infections, but not by major Gram-positive bacteria tested so far, presumably because they do not produce heptose.4Gaudet R.G. Sintsova A. Buckwalter C.M. et al.Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.Science. 2015; 348: 1251-1255Crossref PubMed Scopus (99) Google Scholar, 5Gaudet R.G. Guo C.X. Molinaro R. et al.Innate recognition of intracellular bacterial growth is driven by the TIFA-dependent cytosolic surveillance pathway.Cell Rep. 2017; 19: 1418-1430Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The NLR family pyrin containing 3 (NLRP3) is an important component of innate immunity, and forms a multimeric structure called the "inflammasome" upon activation in immune cells and various other cell types. NLRP3 works as a platform for the cleavage of proforms of IL-1β and IL-18 to generate its active counterparts.22Backert S. Inflammasome signaling and bacterial infections. Springer, Heidelberg2016Crossref Google Scholar The NLRP3 inflammasome is one of the most studied inflammasomes and requires a first signal for priming and a second signal for activation. Generally, TLR engagement with its ligands and subsequent NF-κB activation provides the first signal for increased expression of NLRP3. Different microbial, environmental, and metabolic molecules can function as second signal, but all converge to one function of K+ efflux to activate the inflammasome.23He Y. Zeng M.Y. Yang D. et al.NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux.Nature. 2016; 530: 354-357Crossref PubMed Scopus (641) Google Scholar A very recent study reported the importance of NLRP3 inflammasome on the regulation of inflammatory bowel disease.24Neudecker V. Haneklaus M. Jensen O. et al.Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome.J Exp Med. 2017; 214: 1737-1752Crossref PubMed Scopus (243) Google Scholar It was first described that TIFA plays a crucial role in NLRP3 inflammasome priming and activation.25Lin T.Y. Wei T.W. Li S. et al.TIFA as a crucial mediator for NLRP3 inflammasome.Proc Natl Acad Sci U S A. 2016; 113: 15078-15083Crossref PubMed Scopus (31) Google Scholar In this study, arteries and cultured endothelial cells exposed to mechanical stress and oxidized low-density lipoprotein have increased the activation of sterol regulatory element-binding protein 2 (SREBP2) to enhance the transcription of TIFA and NLRP3. In addition, SREBP2-mediated overexpression of TIFA caused NF-κB activation, which was also contributing to the overexpression of NLRP3 and inflammasome components, such as the inactive proforms of caspase-1 and IL-1β, respectively. Therefore, the SREBP2→TIFA→NF-κB axis worked for the transcriptional activation of NLRP3 inflammasome components, which satisfies the quality of the first signal of inflammasome activation. Moreover, they found that TIFA Thr-9 phosphorylation was mediated by kinase Akt in endothelial cells, which led to TIFAsome formation. Interestingly, in vitro inflammasome reconstitution studies showed that Akt-mediated TIFAsome formation involved in the NLRP3 inflammasome activation, that is, they acted as a second signal.25Lin T.Y. Wei T.W. Li S. et al.TIFA as a crucial mediator for NLRP3 inflammasome.Proc Natl Acad Sci U S A. 2016; 113: 15078-15083Crossref PubMed Scopus (31) Google Scholar Although, this study is the only one to report on this aspect of TIFA, it adds up the quality of this novel innate immune molecule on detecting invasive intracellular pathogens apart from gut microbiome and regulating the homeostasis of intestinal tract, which deserves further investigation in the future. Further studies revealed that TIFA functions are not restricted to innate immunity. Hepatocellular carcinoma (HCC) is one of the most common causes worldwide for cancer-associated mortality in humans. The most common trigger of chronic liver inflammation is viral hepatitis, especially by hepatitis B virus and hepatitis C virus. Inflammatory mediator receptors such as TLR4, TREM-1, and transcription factor ATF4 have been implicated in the development of HCC. A recent study showed that the inflammatory mediator TIFA was down-regulated in HCC compared with normal liver tissue.26Shen W. Chang A. Wang J. et al.TIFA, an inflammatory signaling adaptor, is tumor suppressive for liver cancer.Oncogenesis. 2015; 4: e173Crossref PubMed Scopus (25) Google Scholar Remarkably, the overexpression of TIFA in HCC cell lines caused increased cell death rates when compared with control cells. Corresponding molecular studies showed that TIFA overexpression increased p53 and phospho-p53 in HCC cells to induce cell cycle arrest and apoptosis. However, p53 was not the only involved factor, but a concomitant increase in CDC2 and p21 expression for cell cycle arrest was also observed, which increased G0/G1 cell population and short hairpin RNA–mediated TIFA silencing promoted proliferation. Moreover, TIFA-triggered apoptotic cell death was facilitated through executioner caspase-3, which seems to be controlled by caspase-8. As described, the TIFAsome has activated the NLRP3 inflammasome.25Lin T.Y. Wei T.W. Li S. et al.TIFA as a crucial mediator for NLRP3 inflammasome.Proc Natl Acad Sci U S A. 2016; 113: 15078-15083Crossref PubMed Scopus (31) Google Scholar It is also reported that the noncanonical NLRP3 platform can activate caspase-8.27Chung H. Vilaysane A. Lau A. et al.NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis.Cell Death Differ. 2016; 23: 1331-1346Crossref PubMed Scopus (69) Google Scholar Therefore, NLRP3 could also be involved in the activation of caspase-8 in TIFA-mediated suppression of HCC. In contrast with the findings in HCC, TIFA Thr-9 phosphorylation mediated by the kinase Aurora-A induced a NF-κB–dependent survival pathway in acute myeloid leukemia cells. In addition, TIFA deficiency in acute myeloid leukemia cell lines and isolated primary cells have exhibited down-regulated expression of prosurvival BCL proteins, cytokines, and reduced the effective concentration of chemotherapeutic drugs.28Wei T.W. Wu P.Y. Wu T.J. et al.Aurora A and NF-κB survival pathway drive chemoresistance in acute myeloid leukemia via the TRAF-interacting protein TIFA.Cancer Res. 2017; 77: 494-508Crossref PubMed Scopus (32) Google Scholar These studies demonstrate the varied response of TIFA on controlling different types of cancers. There is no study yet linking bacterial activation of the TIFAsome to the pathogenesis of human cancer. In this regard, it is of potential interest to explore in future if H pylori-mediated TIFAsome activation could contribute to the pathogenesis of gastric cancer and B-cell mucosa-associated lymphoid tissue lymphoma. Microbes produce a great variety of different types of conserved structural components, called PAMPs, which can be sensed by the host.2Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (664) Google Scholar, 3Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (2007) Google Scholar This recognition of "non-self" signatures occurs through host pattern recognition receptors and supports the view that microbe-derived signals are perfect targets to discriminate between self and non-self and trigger innate immunity.1Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb Symp Quant Biol. 1989; 54: 1-13Crossref PubMed Google Scholar, 2Beutler B. Jiang Z. Georgel P. et al.Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.Annu Rev Immunol. 2006; 24: 353-389Crossref PubMed Scopus (664) Google Scholar, 3Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (2007) Google Scholar This is facilitated by distinct downstream signaling cascades leading to the production of proinflammatory cytokines, interferons, and defensins that tailor proper immune responses to particular microbes. It is becoming increasingly clear that multiple PAMPs are recognized by components of the innate immune system, which informs the host to both the identity and infection risk derived from a given microbe. In this regard, HBP serves as a flexible new indicator of various Gram-negative species and lifestyles. Previous studies focused on a selection of invasive and extracellular pathogens including S flexneri, S enterica, and N meningitidis.6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar HBP release by bacteria replicating within the host cytosol, for example, seems to be the limiting component, which determines whether the ALPK1→TIFA signaling axis is engaged or not, and the relative amount of HBP present seems to determine the immunologic interpretation of the danger (Figure 2A). The extracellular pathogen N meningitidis effectively liberates HBP during growth and/or releases it by lysis, which seems to be delivered into the cell through endocytosis.6Milivojevic M. Dangeard A.S. Kasper C.A. et al.ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria.PLoS Pathog. 2017; 13: e1006224Crossref PubMed Scopus (64) Google Scholar However, it remains unclear if HBP can directly bind TIFA, ALPK1, or any other upstream signaling factor. Also, the phosphorylation target(s) of ALPK1 in the TIFA cascade remain to be investigated, because it is not clear that this kinase phosphorylates TIFA itself. In addition, is not yet identified if extracellular HBP release may trigger a "low-level" alert of Gram-negative bacteria being present in the tissue, which requires further investigation. A remarkable new example of HBP delivery has been provided by research on the extracellular pathogen H pylori.7Stein S.C. Faber E. Bats S.H. et al.Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis.PLoS Pathog. 2017; 13: e1006514Crossref PubMed Scopus (77) Google Scholar, 8Gall A. Gaudet R.G. Gray-Owen S.D. et al.TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection.mBio. 2017; 8 (e01168–17)Crossref Scopus (80) Google Scholar, 9Zimmermann S. Pfannkuch L. Al-Zeer M. et al.ALPK1 and TIFA dependent innate immune response triggered by the H. pylori type IV secretion.Cell Rep. 2017; 20: 2384-2395Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The results reported by 3 independent groups are in line with the hypothesis that HBP can be injected into the host cytosol by a T4SS. This is the first report of a sugar being transported through a T4SS pilus. How this works in detail and if additional T4SS-expressing bacterial pathogens such as Bartonella, Coxiella, Legionella, and others can also deliver HBP in a similar fashion awaits further investigation. Thus, HBP is a fascinating newly identified PAMP, which induces TIFAsome formation to modulate the innate and adaptive immune system, and aids in the effective surveillance of the mucosal surfaces and in maintaining homeostasis.
Referência(s)