Cell membrane Complex Enzyme Eukaryotic cell or cell component Microbe-host cell complex Microorganism or its component Other Other -- ion Pathway or action Protein Protein or gene Protein or gene complex Protein or protein complex Bacterial membrane or virus envelope Cell membrane Cytoplasm Eukaryotic cell or cell component Extracellular Golgi Golgi membrane Intercellular Intracellular Mitochondria Nucleocapsid/Cytoplasm Organelle Organelle -- Cell membrane Organelle -- Endoplasmic reticulum Organelle -- ER Organelle -- Golgi Organelle -- Golgi membrane Organelle -- Nucleus Organelle -- Phagolysosome Organelle -- Phagosome Organelle -- Ribosome Other Phagolysosome Phagosome Chaperone Defense, immunity protein Enzyme Enzyme activator Enzyme inhibitor Genomic S segment Infection Ligand binding or carrier Motor Nucleic acid binding Other Signal transducer Toxicity Transcription factor binding Transcription regulation Transporter Unknown IC Inferred by Curator IDA Inferred from Direct Assay IEA Inferred from Electronic Annotation IEP Inferred from Expression Pattern IGI Inferred from Genetic Interaction IMP Inferred from Mutant Phenotype IPI Inferred from Physical Interaction ISS Inferred from Sequence or Structural Similarity NAS Non-traceable Author Statement ND No biological Data available RCA inferred from Reviewed Computational Analysis TAS Traceable Author Statement NR Not Recorded Sandvig K Toxicon : official journal of the International Society on Toxinology Shiga toxins 2001 11595626 PubMed Sandvig K, van Deurs B Physiological reviews Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin 1996 8874490 PubMed Garred O, Dubinina E, Polesskaya A, Olsnes S, Kozlov J, Sandvig K The Journal of biological chemistry Role of the disulfide bond in Shiga toxin A-chain for toxin entry into cells 199725 9111051 PubMed Bahrani FK, Sansonetti PJ, Parsot C Infection and immunity Secretion of Ipa proteins by Shigella flexneri: inducer molecules and kinetics of activation 1997 9316999 PubMed Magdalena J, Hachani A, Chamekh M, Jouihri N, Gounon P, Blocker A, Allaoui A Journal of bacteriology Spa32 regulates a switch in substrate specificity of the type III secreton of Shigella flexneri from needle components to Ipa proteins 2002 12057936 PubMed Blocker A, Gounon P, Larquet E, Niebuhr K, Cabiaux V, Parsot C, Sansonetti P The Journal of cell biology The tripartite type III secreton of Shigella flexneri inserts IpaB and IpaC into host membranes 19991 10545510 PubMed De Geyter C, Wattiez R, Sansonetti P, Falmagne P, Ruysschaert JM, Parsot C, Cabiaux V European journal of biochemistry / FEBS Characterization of the interaction of IpaB and IpaD, proteins required for entry of Shigella flexneri into epithelial cells, with a lipid membrane 2000 10971588 PubMed Tran Van Nhieu G, Caron E, Hall A, Sansonetti PJ The EMBO journal IpaC induces actin polymerization and filopodia formation during Shigella entry into epithelial cells 199915 10369666 PubMed Bourdet-Sicard R, Rudiger M, Jockusch BM, Gounon P, Sansonetti PJ, Nhieu GT The EMBO journal Binding of the Shigella protein IpaA to vinculin induces F-actin depolymerization 19991 10545097 PubMed Fernandez IM, Silva M, Schuch R, Walker WA, Siber AM, Maurelli AT, McCormick BA The Journal of infectious diseases Cadaverine prevents the escape of Shigella flexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil transepithelial signaling 200115 11517436 PubMed Magdalena J, Goldberg MB Cell motility and the cytoskeleton Quantification of Shigella IcsA required for bacterial actin polymerization 2002 11977093 PubMed Monack DM, Theriot JA Cellular microbiology Actin-based motility is sufficient for bacterial membrane protrusion formation and host cell uptake 2001 11553015 PubMed Guichon A, Hersh D, Smith MR, Zychlinsky A Journal of bacteriology Structure-function analysis of the Shigella virulence factor IpaB 2001 11157939 PubMed Antón IM, Jones GE, Wandosell F, Geha R, Ramesh N Trends in cell biology WASP-interacting protein (WIP): working in polymerisation and much more 2007 17949983 PubMed Tarragó-Trani MT, Storrie B Advanced drug delivery reviews Alternate routes for drug delivery to the cell interior: pathways to the Golgi apparatus and endoplasmic reticulum 2007 17669543 PubMed Kenjale R, Wilson J, Zenk SF, Saurya S, Picking WL, Picking WD, Blocker A The Journal of biological chemistry The needle component of the type III secreton of Shigella regulates the activity of the secretion apparatus 2005 16227202 PubMed Nhieu GT, Izard T The EMBO journal Vinculin binding in its closed conformation by a helix addition mechanism 2007 17932491 PubMed Ramarao N, Le Clainche C, Izard T, Bourdet-Sicard R, Ageron E, Sansonetti PJ, Carlier MF, Tran Van Nhieu G FEBS letters Capping of actin filaments by vinculin activated by the Shigella IpaA carboxyl-terminal domain 2007 17289036 PubMed Hamiaux C, van Eerde A, Parsot C, Broos J, Dijkstra BW EMBO reports Structural mimicry for vinculin activation by IpaA, a virulence factor of Shigella flexneri 2006 16826238 PubMed Shiga Toxin secretion by bacterial cells Function: Transporter. Shiga Toxin secretion by bacterial cells(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Shiga Toxin realease ( Subunit A - Subunit B (pentameric ring)) Function: Enzyme inhibitor. The Shiga toxin is composed of a single catalytic subunit A that is associated with a pentameric ring formed by subunit B(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Subunit B - Receptor Gb3 interaction on host cell surface (Gb3 - Globotiaosyl ceramide) Function: Enzyme inhibitor. The B subunit binds globotriaosyl ceramide (Gb3) glycolipid receptor on cell surfaces(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Endocytosis. Shiga Toxin (Subunit B) - membrane interaction Function: Enzyme inhibitor. Following binding, toxin uptake occurs by various receptor-mediated endocytic pathways (Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997). Targeting properties of shiga toxins reside in their B subunit (Tarragó-Trani and Storrie, 2007). Vesicles containing Shiga Toxin. Shiga Toxin transport to the Trans-Golgi Network Function: Enzyme inhibitor. Endosomes are transported to the Trans-Golgi Network (TGN)(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Trans-Golgi Network. Shiga Toxin-Subunit A nicking by protease Furin Function: Enzyme. Followed by transport to the Trans-Golgi Network and endoplasmic reticulum (ER), the A subunit is cleaved by furin in the Trans-Golgi Network(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Golgi Apparatus. Shiga Toxin-Subunit A nicking by protease Furin Function: Enzyme. Followed by transport to the Golgi apparatus and endoplasmic reticulum (ER), the A subunit is cleaved by furin in the endosomes/Golgi apparatus (Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997). Endoplasmic Reticulum. Shiga Toxin-Release of fragment A1(enzymatically active) from fragment A2 Function: Enzyme. The A1 enzymatically active part is released from the A2 fragment in the ER (Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997). Ribosome. The A1 fragment cleaves the N-glycosidic bond in 28S rRNA Function: Nucleic acid binding. The A1 fragment cleaves the N-glycosidic bond, removing one adenine from adenosine in position 4324 from the 5' terminus in 28S rRNA of the 60S ribosomal subunit(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Inhibition of binding of aminoacyl - tRNA Function: Nucleic acid binding. Inhibition of binding of aminoacyl-tRNA to the 60S ribosomal subunit (Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997). Protein synthesis blocking and death of intoxicated cells Function: . This action blocks protein synthesis, resulting in death of intoxicated cells. The B subunit is capable of triggering apoptosis, mechanism not understood(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Furin Function: Enzyme. Furin is a critical enzyme for the processing of Shiga toxin (cleavage of Shiga toxin)(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Type III Secretion System Function: Transporter. Shigella virulence proteins are secreted via the type III secretion apparatus (TTSS) across the envelope.(Bahrani et al., 1997)(Magdalena et al., 2002)(Blocker et al., 1999) MxiH, MxiI secretion via TTSS. MxiH-MxiI structure formation Function: Transporter. MxiH (Membrane Expression of Invasion), MxiI proteins are secreted via the type III secretion apparatus.(Bahrani et al., 1997)(Magdalena et al., 2002)(Blocker et al., 1999) TTSS-MxiH(n), TTSS-MxiI(n). Needle like structure formation Function: Transporter. Mxi proteins form an extension on the bacterial surface enabling the transfer of the Ipa proteins (Invasion Plasmid Antigen) directly into the host cell.(Bahrani et al., 1997)(Magdalena et al., 2002)(Blocker et al., 1999) IpaB, IpaC, IpaD translocation via TTSS-MxiH-MxiI (TTSS-Mxi) complex Function: Transporter. IpaB, C, D proteins are translocated directly into the host plasma membrane and associated with infected host cell membrane.(Bahrani et al., 1997)(Magdalena et al., 2002)(Blocker et al., 1999) TTSS-MxiH-MxiI-IpaB-IpaD (TTSS-Mxi-Ipa) structure formation Function: Transporter. This structure controls the translocation of proteins through the type III secretion apparatus.(De et al., 2000) IpaB-IpaD complex. Control proteins flux Function: Transporter. This complex controls the flux of proteins through the type III secreton systems.(De et al., 2000) IpaB-IpaC complex formation Function: Transporter. IpaB and IpaC form a complex which inserts into the host cell membrane.(De et al., 2000)(Tran et al., 1999) IpaC modulates Cdc 42-dependent Filopodial formation Function: . Shigella cells form filopodial structures that eventually give rise to lamellipodial structure. The mechanisms involved in the activation of Cdc42 and Rac by IpaC are currently unknown.(De et al., 2000)(Tran et al., 1999) IpaC modulates Rac1-dependent Lamellipodial formation Function: . Shigella cells form filopodial structures that eventually give rise to lamellipodial structure. The mechanisms involved in the activation of Cdc42 and Rac by IpaC are currently unknown.(De et al., 2000)(Tran et al., 1999) IpaA translocation via TTSS-Mxi-Ipa structure Function: . IpaA is injected into the host cell cytosol (Bourdet-Sicard et al., 1999). The needle component of the type III secreton (TTSS) of Shigella regulates the activity of the secretion apparatus, which serves to transfer bacterial proteins into host cells. IpaA and IpgD, two supplementary effectors of cell invasion, are transferred into the host cytoplasm. TTSS activation requires direct contact of the external distal tip of the apparatus with the host cell. The monomeric unit of the Shigella flexneri needle, MxiH, forms a superhelical assembly. The needle directly controls the activity of the TTSS and suggest that it may be used to "sense" host cells (Kenjale et al., 2005). IpaA-Vinculin complex formation Function: . This process results from the binding of IpaA to vinculin (a cytoskeleton-associated protein) (Bourdet-Sicard et al., 1999). Vinculin links integrin receptors to the actin cytoskeleton by binding to talin, is held in an inactive closed-clamp conformation through hydrophobic interactions between its head and tail domains, and activation depends on severing this interaction by talin and IpaA and allowing vinculin to bind to its other partners. The lower affinity VBS of IpaA can also bind to the adjacent C-terminal four-helical bundle of vinculin's head domain through a helix addition mechanism. These hydrophobic interactions do not alter the conformation of this helical bundle, and the architecture of the complex suggests that IpaA can simultaneously interact with both of the four-helical bundle domains of vinculin's N-terminus to stabilize vinculin-IpaA interactions (Nhieu and Izard, 2007). Upon bacterial-cell contact, the type III bacterial effector IpaA binds to the cytoskeletal protein vinculin to promote actin reorganization required for efficient bacterial uptake. The last 74 C-terminal residues of IpaA bind to vinculin and promotes its association with actin filaments. IpaA regulates actin polymerisation/depolymerisation at sites of Shigella invasion by modulating the barbed end capping activity of vinculin (Ramarao et al., 2007). IpaA is injected into the epithelial cell by a TTSS and recruits vinculin to regulate actin polymerization at the site of entry. IpaA has two vinculin-binding sites that simultaneously bind two VD1 molecules. The interaction of IpaA with VD1 is highly similar to the interaction of the endogenous, eukaryotic proteins talin and alpha-actinin with VD1, showing that Shigella uses a structural mimicry strategy to activate vinculin (Hamiaux et al., 2006). Actin filaments depolymerization. Lamellipodial formation Function: . IpaA-Vinculin structure results in very short actin filaments, indicating that the IpaA-Vinculin complex induces actin depolymerization and the Lamellipodial formation (Bourdet-Sicard et al., 1999). WASP, N-WASP, and WIP play significant roles in the regulation of actin polymerisation, allowing the migration of cells and the movement of Shigella organisms. The activity and stability of WASP is regulated by WIP during the formation of actin-rich structures, including lamellipodia (Antón et al., 2007). Shigella-induced cytoskeletal rearrangements Function: . This results in a macropinocytic pocket which engulfs the microorganism.(Tran et al., 1999) Shigella internalization in vacuole Function: . This process induces and modulates the macropinocytic vacuole.(Tran et al., 1999)(Fernandez et al., 2001) IpaB and IpaC disrupt the vacuolar membrane Function: . IpaB and IpaC complex induces the membrane lysis.(Fernandez et al., 2001) Escape of Shigella from the vacuole into the cytoplasm Function: . Lysis of the vacuolar membrane allows escape of Shigella into the cytoplasm of the newly infected cells (Fernandez et al., 2001). Expression of IcsA protein on Shigella surface Function: . IcsA protein is exported into the bacterial outer membrane and required to induce actin polymerization.(Fernandez et al., 2001)(Magdalena et al., 2002) Movement within the cytoplasm is mediated by IcsA Function: . Movement within the cytoplasm is mediated by IcsA protein. IcsA is essential for proper assembly of the comet tail and movement inside the cell cytoplasm.(Magdalena et al., 2002)(Monack et al., 2001) Shigella intracellular and intercellular spread Function: . IcsA achieves the actin-based motility of Shigella and permits its passage from one cell to another. Actin-based motility allows cell-to-cell spread in a process that involves the cellular junction.(Monack et al., 2001) Shigella induction of apoptosis Function: . Essential events in the pathogenesis of Shigella infection result in induction of apoptosis in macrophages.(Guichon et al., 2001)