BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1904150001?filename=Hannig(geb%20Scheidel)2016%20-%20In%20Silico%20Knockout%20Studies%20of%20Xenophagic%20Capturing%20of%20Salmonella,%20Petri%20Nets.xmlprimaryOK200Nasrin Alikhani ChamgordaniNon-curatedpetri netL3V1https://www.ebi.ac.uk/biomodels/MODEL190415000127906974falseBioModelsSBMLModelsScheidel2016 In Silico Knockout Studies of Xenophagy Capturing of Salmonella2016MODEL1904150001Non KineticScheidel J, Amstein L, Ackermann J, Dikic I, Koch IScheidel J27906974,
The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway.. 12, 12.
Molecular Bioinformatics, Institute of Computer Science, Johann Wolfgang Goethe-University Frankfurt am Main, Frankfurt am Main, Germany.nasrin.alikhani7@gmail.comThe degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway.Several species of pathogenic bacteria replicate within an intracellular vacuolar niche. Bacteria that escape into the cytosol are captured by the autophagic pathway and targeted for lysosomal degradation, representing a defense against bacterial exploitation of the host cytosol. Autophagic capture of Salmonella Typhimurium occurs predominantly via generation of a polyubiquitin signal around cytosolic bacteria, binding of adaptor proteins, and recruitment of autophagic machinery. However, the components mediating bacterial target selection and ubiquitination remain obscure. We identify LRSAM1 as the E3 ligase responsible for anti-Salmonella autophagy-associated ubiquitination. LRSAM1 localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal; these functions require LRSAM1's leucine-rich repeat and RING domains, respectively. Using cells from LRSAM1-deficient individuals, we confirm that LRSAM1 is required for ubiquitination associated with intracellular bacteria but dispensable for ubiquitination of aggregated proteins. LRSAM1 is therefore a bacterial recognition protein and ubiquitin ligase that defends the cytoplasm from invasive pathogens.Autophagy, a cellular degradative pathway, plays a key role in protecting the cytosol from bacterial colonization, but the mechanisms of bacterial recognition by this pathway are unclear. Autophagy is also known to degrade cargo tagged by ubiquitinated proteins, including aggregates of misfolded proteins, and peroxisomes. Autophagy of ubiquitinated cargo requires p62 (also known as SQSTM1), an adaptor protein with multiple protein-protein interaction domains, including a ubiquitin-associated (UBA) domain for ubiquitinated cargo binding and an LC3 interaction region (LIR) for binding the autophagy protein LC3. Previous studies demonstrated that the intracellular bacterial pathogen Salmonella typhimurium is targeted by autophagy during infection of host cells. Here we show that p62 is recruited to S. typhimurium targeted by autophagy, and that the recruitment of p62 is associated with ubiquitinated proteins localized to the bacteria. Expression of p62 is required for efficient autophagy of bacteria, as well as restriction of their intracellular replication. Our studies demonstrate that the surveillance of misfolded proteins and bacteria occurs via a conserved pathway, and they reveal a novel function for p62 in innate immunity.Autophagy is a process whereby a double-membrane structure (autophagosome) engulfs unnecessary cytosolic proteins, organelles, and invading pathogens and delivers them to the lysosome for degradation. We examined the fate of cytosolic Salmonella targeted by autophagy and found that autophagy-targeted Salmonella present in the cytosol of HeLa cells correlates with intracellular bacterial replication. Real-time analyses revealed that a subset of cytosolic Salmonella extensively associates with autophagy components p62 and/or LC3 and replicates quickly, whereas intravacuolar Salmonella shows no or very limited association with p62 or LC3 and replicates much more slowly. Replication of cytosolic Salmonella in HeLa cells is significantly decreased when autophagy components are depleted. Eventually, hyperreplication of cytosolic Salmonella potentiates cell detachment, facilitating the dissemination of Salmonella to neighboring cells. We propose that Salmonella benefits from autophagy for its cytosolic replication in HeLa cells. IMPORTANCE As a host defense system, autophagy is known to target a population of Salmonella for degradation and hence restricting Salmonella replication. In contrast to this concept, a recent report showed that knockdown of Rab1, a GTPase required for autophagy of Salmonella, decreases Salmonella replication in HeLa cells. Here, we have reexamined the fate of Salmonella targeted by autophagy by various cell biology-based assays. We found that the association of autophagy components with cytosolic Salmonella increases shortly after initiation of intracellular bacterial replication. Furthermore, through a live-cell imaging method, a subset of cytosolic Salmonella was found to be extensively associated with autophagy components p62 and/or LC3, and they replicated quickly. Most importantly, depletion of autophagy components significantly reduced the replication of cytosolic Salmonella in HeLa cells. Hence, in contrast to previous reports, we propose that autophagy facilitates Salmonella replication in the cytosol of HeLa cells.Alcohol consumption leads to the production of the highly reactive ethanol metabolite, acetaldehyde, which may affect intestinal tight junctions and increase paracellular permeability. We examined the effects of elevated acetaldehyde within the gastrointestinal tract on the permeability and bioavailability of hydrophilic markers and drug molecules of variable molecular weight and geometry. In vitro permeability was measured unidirectionally in Caco-2 and MDCKII cell models in the presence of acetaldehyde, ethanol, or disulfiram, an aldehyde dehydrogenase inhibitor, which causes acetaldehyde formation when coadministered with ethanol in vivo. Acetaldehyde significantly lowered transepithelial resistance in cell monolayers and increased permeability of the low-molecular-weight markers, mannitol and sucrose; however, permeability of high-molecular-weight markers, polyethylene glycol and inulin, was not affected. In vivo permeability was assessed in male Sprague-Dawley rats treated for 6 days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, whereas that of paclitaxel was increased upon acetaldehyde exposure. Although disulfiram has been shown to inhibit multidrug resistance-1 P-glycoprotein (P-gp) in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by coadministration of disulfiram. In conclusion, we demonstrate that acetaldehyde significantly modulates tight junctions and paracellular permeability in vitro as well as the oral bioavailability of low-molecular-weight hydrophilic probes and therapeutic molecules in vivo even when these molecules are substrates for efflux transporters. These studies emphasize the significance of ethanol metabolism and drug interactions outside of the liver.Selective autophagy can be mediated via receptor molecules that link specific cargoes to the autophagosomal membranes decorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy.Autophagy defends the mammalian cytosol against bacterial infection. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.Cell-autonomous innate immune responses against bacteria attempting to colonize the cytosol of mammalian cells are incompletely understood. Polyubiquitylated proteins can accumulate on the surface of such bacteria, and bacterial growth is restricted by Tank-binding kinase (TBK1). Here we show that NDP52, not previously known to contribute to innate immunity, recognizes ubiquitin-coated Salmonella enterica in human cells and, by binding the adaptor proteins Nap1 and Sintbad, recruits TBK1. Knockdown of NDP52 and TBK1 facilitated bacterial proliferation and increased the number of cells containing ubiquitin-coated salmonella. NDP52 also recruited LC3, an autophagosomal marker, and knockdown of NDP52 impaired autophagy of salmonella. We conclude that human cells utilize the ubiquitin system and NDP52 to activate autophagy against bacteria attempting to colonize their cytosol.In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response.The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.Abstracts of the 36th Annual Meeting of the Society for Epidemiologic Research. Atlanta, Georgia, USA. June 11-14, 2003.Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.In Silico Knockout Studies of Xenophagic Capturing of Salmonella.Autophagy facilitates Salmonella replication in HeLa cells.The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium.Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth.Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity.The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway.The ethanol metabolite acetaldehyde increases paracellular drug permeability in vitro and oral bioavailability in vivo.Scheidel Jennifer J, Amstein Leonie L, Ackermann Jörg J, Dikic Ivan I, Koch Ina IYu Hong B HB, Croxen Matthew A MA, Marchiando Amanda M AM, Ferreira Rosana B R RB, Cadwell Ken K, Foster Leonard J LJ, Finlay B Brett BBWild Philipp P, Farhan Hesso H, McEwan David G DG, Wagner Sebastian S, Rogov Vladimir V VV, Brady Nathan R NR, Richter Benjamin B, Korac Jelena J, Waidmann Oliver O, Choudhary Chunaram C, Dötsch Volker V, Bumann Dirk D, Dikic Ivan IFisher Scott J SJ, Swaan Peter W PW, Eddington Natalie D NDHuett Alan A, Heath Robert J RJ, Heath Robert J RJ, Begun Jakob J, Sassi Slim O SO, Baxt Leigh A LA, Vyas Jatin M JM, Goldberg Marcia B MB, Xavier Ramnik J RJThurston Teresa L M TL, Wandel Michal P MP, von Muhlinen Natalia N, Foeglein Agnes A, Randow Felix FThurston Teresa L M TL, Ryzhakov Grigory G, Bloor Stuart S, von Muhlinen Natalia N, Randow Felix FNg Aylwin C Y AC, Eisenberg Jason M JM, Heath Robert J W RJ, Heath Robert J W RJ, Huett Alan A, Robinson Cory M CM, Nau Gerard J GJ, Xavier Ramnik J RJZheng Yiyu T YT, Shahnazari Shahab S, Brech Andreas A, Lamark Trond T, Johansen Terje T, Brumell John H JHSamonella.projections, multicellular organismal catabolic process, single-organism catabolic process, host organism, nucleocytoplasm, SCV, Immune Systems, Epithelial Cell, ER-Phagy, determination, Vacuole, NetrinA, D430049E23Rik, TBK1, Glandular, ALS12, temporal, 12, autophagy, 2, 4, Elkh, Eubacteria, High Mobility Protein 20, Salmonella enterica serovar Typhimurium, catabolism, EK6, Ubiquitin-related 1, Adenomatous Epithelial, present in organism, Sap-2, [5], neuroendocrine tumour, APF-1, Immune, Bacteria <bacteria>, Solute carrier family 6 member 2, ER Phagy, Prokaryotae, papilla, Nucleophagy, CT27014, NET1, SLC6A5, 1200008B05Rik, Procaryotae, netA, intracellular, Transitional Epithelial Cell, Elk, ELK, anatomical protrusion, Papers, HIP7, Neuronally-expressed EPH-related tyrosine kinase, IKBKB, lamina, IKBKA, flanges, Adenomatous, SAP2, 9330129L11, Squamous, Ribophagy, parasitophorous vacuole, Transitional Epithelial, CEP52, results, neuroendocrine neoplasm, Literatures, Norepinephrine transporter, Reticulophagy, shelf, Autophagocytosis, Cellular, EPH-like kinase 6, prokaryotes, internal to cell, activation, Ubiq, GLC1E, Ubiquitin, Adenomatous Epithelial Cell, Adenomatous Epithelial Cells, Squamous Cell, breakdown, Autophagy, shelves, System, Human Ubiquitin, hEK6, pathogen-occupied vacuole, projection, ridge, experimental procedures, organ system, DmelCG18657, IKK-2, spine, IKK-1, Cells, HYPL, Cytosols, NAK, :i:1, Prokaryota, 12:i:1, Salmonella-containing vacuole, AW488255, Salmonella typhi-murium, vacuolar carboxypeptidase Y, Samonella, experimental, lamellae, NRP, STK12, Lipophagy, ATP Dependent Proteolysis Factor 1, Glandular Epithelial, eubacteria, Ubiquitin carboxyl extension protein 80, bacterium-containing vacuole, nak, process of organ, body system, protrusion, netrin, Human, lamella, Squamous Epithelial Cells, Hek6, Cellular Autophagy, Cek6, HMG-20, system, ubiquitin-like protein modifier, Bacillus typhimurium, Squamous Epithelial, ENSMUSG00000074119, Epithelial, protoplasm, Erp, APUDoma, ERP, anatomical systems, methods, protoplast, experimental 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Neuronally-expressed EPH-related tyrosine kinase, IKBKB, lamina, IKBKA, flanges, Adenomatous, SAP2, 9330129L11, Squamous, Ribophagy, Transitional Epithelial, CEP52, neuroendocrine neoplasm, Literatures, organism, epithelial, Norepinephrine transporter, Reticulophagy, shelf, Autophagocytosis, Cellular, EPH-like kinase 6, TU15B, activation, Ubiq, GLC1E, dBest1, Ubiquitin, Adenomatous Epithelial Cell, Adenomatous Epithelial Cells, Squamous Cell, whole organism, Autophagy, shelves, dbest1, Human Ubiquitin, hEK6, projection, ridge, organ system, DmelCG18657, IKK-2, spine, IKK-1, Koerper, Cells, HYPL, NAK, AW488255, multi-cellular organism, Samonella, conformation, lamellae, NRP, STK12, Lipophagy, ATP Dependent Proteolysis Factor 1, Glandular Epithelial, Ubiquitin carboxyl extension protein 80, nak, anon-WO0118547.380, process of organ, body system, protrusion, netrin, Human, lamella, Squamous Epithelial Cells, Hek6, Cellular Autophagy, Cek6, HMG-20, system, ubiquitin-like protein modifier, Squamous Epithelial, ENSMUSG00000074119, Epithelial, Erp, APUDoma, ERP, anatomical systems, VMD2, nutrients, Tyrosine-protein kinase receptor EPH-2, uniform, AI462036, TANK-binding kinase 1 activity, ridges, BMD, ATP:IkappaB protein phosphotransferase activity, 40S ribosomal protein S27a, 2.7.10.1, IKK, Epithelial Cells, Transitional Epithelial Cells, Etrp, ubiquitin, NAT1, species, glutamine:preQ0-tRNA amidinotransferase, laminae, Squamous Epithelial Cell, protein tagging activity, AW048562, relational structural quality, Net, NET, Glandular Epithelial Cell, ikappaB kinase activity, incidence, RP50, Transitional, Squamous Cells, nutrient, constant, data, C130099E04Rik, body, anatomical process, inhibitor of NF-kappaB kinase activity, EPH tyrosine kinase 2, whole body, selective autophagy, neuroendocrine tumor, net, Cell, TFIIIA-INTP, CHUK, Ubiquitin A-52 residue ribosomal protein fusion product 1, Cuboidal Glandular Epithelial Cells, Ubiquitin-related 2, T2K, Columnar Glandular Epithelial Cells, ATP-Dependent Proteolysis Factor 1, connected anatomical system, flange, organ process, epitheliocyte, covalent modifier, inhibitor of NFkappaB kinase activity, Dbest, FIP2, best, Glandular Epithelial Cells, CG18657, processes, process, 60S ribosomal protein L40, EPHT2, protein tag, t2k, 4930441O07Rik, processus, Ubiquitin-related, regulation, BEST, netrin Abacteria, ER-Phagy, inhibitor of NF-kappaB kinase activity, IKBKB, IKBKA, STK12, TBK1, Lipophagy, ATP Dependent Proteolysis Factor 1, selective autophagy, eubacteria, Ubiquitin carboxyl extension protein 80, nak, Ribophagy, CEP52, NDP52, Human, autophagy, CHUK, Prokaryota., Ubiquitin A-52 residue ribosomal protein fusion product 1, Reticulophagy, Ubiquitin-related 2, T2K, Autophagocytosis, Cellular Autophagy, Cellular, HMG-20, prokaryotes, ATP-Dependent Proteolysis Factor 1, ubiquitin-like protein modifier, Ubiq, Ubiquitin, covalent modifier, inhibitor of NFkappaB kinase activity, Eubacteria, High Mobility Protein 20, Autophagy, Human Ubiquitin, AI462036, TANK-binding kinase 1 activity, Ubiquitin-related 1, ATP:IkappaB protein phosphotransferase activity, Monera, APF-1, 40S ribosomal protein S27a, IKK, Bacteria <bacteria>, IKK-2, 60S ribosomal protein L40, IKK-1, protein tag, ER Phagy, Prokaryotae, prokaryote, t2k, Nucleophagy, ubiquitin, 1200008B05Rik, Ubiquitin-related, fungi, Procaryotae, AW048562, NAK, protein tagging activity, ikappaB kinase activityfalseScheidel2016 - In Silico Knockout Studies of Xenophagy Capturing of Salmonella
Xenophagy, also known as antibacterial autophagy, is a process of capturing and eliminating cytosolic pathogens, like Salmonella. Salmonella is the best-studied model organism for xenophagy. We present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data and contains all known processes of Salmonella xenophagy in epithelial. The model comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. The Petri net is connected, covered by T-invariants, and each T-invariant has a meaningful biological interpretation. We checked the model structure for consistencies and correctness. We found 16 basic functional modules, which describe different pathways of the autophagic capturing of Salmonella and reflect the basic dynamics of the system. The PN model of Salmonella xenophagy comprises 61 places, including nine logical places, and 69 transitions connected by 184 arcs.
2020-04-092020-04-092019-04-15MODEL1904150001K14381K06832R-HSA-5678490R-HSA-5675790R-HSA-5675868R-HSA-5672817R-HSA-165680R-HSA-5683925hsa04120EBI-6115370EBI-12521931EBI-699957727906974198207082161704119812211246182511281221119820208222463242061606323245322T00065GO:0006412GO:0005776GO:0051259GO:0000045GO:0016236GO:0034497GO:0051673GO:0085020GO:0044314GO:0034198GO:0097178C00407Q9BVC4P42345O75385O75143Q8N122Q8TDY2Q9BSB4A7MCY6Q9Y4X5Q6UWE0Q13137Q96CV9Q96CV7Q9UHD2Q9GZQ8O95166Q9H492Q9H0R8Q9BXW4P605202JY75WQ45Z7L4XKL57ZL5EOF3VVW2ULE5B834GXL