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 Riendeau CJ, Kornfeld H Infection and immunity THP-1 cell apoptosis in response to Mycobacterial infection 2003 12496173 PubMed Spira A, Carroll JD, Liu G, Aziz Z, Shah V, Kornfeld H, Keane J American journal of respiratory cell and molecular biology Apoptosis genes in human alveolar macrophages infected with virulent or attenuated Mycobacterium tuberculosis: a pivotal role for tumor necrosis factor 2003 12748057 PubMed Sly LM, Hingley-Wilson SM, Reiner NE, McMaster WR Journal of immunology (Baltimore, Md. : 1950) Survival of Mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1 2003 12496428 PubMed Abarca-Rojano E, Rosas-Medina P, Zamudio-Cortéz P, Mondragón-Flores R, Sánchez-García FJ Scandinavian journal of immunology Mycobacterium tuberculosis virulence correlates with mitochondrial cytochrome c release in infected macrophages 2003 14507307 PubMed Perskvist N, Long M, Stendahl O, Zheng L Journal of immunology (Baltimore, Md. : 1950) Mycobacterium tuberculosis promotes apoptosis in human neutrophils by activating caspase-3 and altering expression of Bax/Bcl-xL via an oxygen-dependent pathway 2002 12055253 PubMed Ozeki Y, Kaneda K, Fujiwara N, Morimoto M, Oka S, Yano I Infection and immunity In vivo induction of apoptosis in the thymus by administration of mycobacterial cord factor (trehalose 6,6'-dimycolate) 1997 9125563 PubMed Hamasaki N, Isowa K, Kamada K, Terano Y, Matsumoto T, Arakawa T, Kobayashi K, Yano I Infection and immunity In vivo administration of mycobacterial cord factor (Trehalose 6, 6'-dimycolate) can induce lung and liver granulomas and thymic atrophy in rabbits 2000 10816531 PubMed Nuzzo I, Galdiero M, Bentivoglio C, Galdiero R, Romano Carratelli C The Journal of infection Apoptosis modulation by mycolic acid, tuberculostearic acid and trehalose 6,6'-dimycolate 2002 12099729 PubMed Ciaramella A, Cavone A, Santucci MB, Garg SK, Sanarico N, Bocchino M, Galati D, Martino A, Auricchio G, D'Orazio M, Stewart GR, Neyrolles O, Young DB, Colizzi V, Fraziano M The Journal of infectious diseases Induction of apoptosis and release of interleukin-1 beta by cell wall-associated 19-kDa lipoprotein during the course of mycobacterial infection 2004 15319868 PubMed López M, Sly LM, Luu Y, Young D, Cooper H, Reiner NE Journal of immunology (Baltimore, Md. : 1950) The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis through Toll-like receptor-2 2003 12594264 PubMed Ciaramella A, Martino A, Cicconi R, Colizzi V, Fraziano M Cell death and differentiation Mycobacterial 19-kDa lipoprotein mediates Mycobacterium tuberculosis-induced apoptosis in monocytes/macrophages at early stages of infection 2000 11270362 PubMed Rojas M, García LF, Nigou J, Puzo G, Olivier M The Journal of infectious diseases Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca+2-dependent cell signaling 2000 10882603 PubMed Maiti D, Bhattacharyya A, Basu J The Journal of biological chemistry Lipoarabinomannan from Mycobacterium tuberculosis promotes macrophage survival by phosphorylating Bad through a phosphatidylinositol 3-kinase/Akt pathway 2001 11020382 PubMed Dao DN, Kremer L, Guérardel Y, Molano A, Jacobs WR Jr, Porcelli SA, Briken V Infection and immunity Mycobacterium tuberculosis lipomannan induces apoptosis and interleukin-12 production in macrophages 2004 15039328 PubMed Guérardel Y, Maes E, Briken V, Chirat F, Leroy Y, Locht C, Strecker G, Kremer L The Journal of biological chemistry Lipomannan and lipoarabinomannan from a clinical isolate of Mycobacterium kansasii: novel structural features and apoptosis-inducing properties 2003 12829695 PubMed Ghosh S, Pal S, Das S, Dasgupta SK, Majumdar S FEMS immunology and medical microbiology Lipoarabinomannan induced cytotoxic effects in human mononuclear cells 1998 9718207 PubMed IL10 Function: Signal transducer. The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. sTNFR2 Function: Ligand binding or carrier. MYD88 Function: Signal transducer. TLR-4 Function: Ligand binding or carrier. The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes. It has been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Also, several transcript variants of this gene have been found, but the protein coding potential of most of them is uncertain. LPS Function: Chaperone. TNF-alpha Function: Ligand binding or carrier. This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine. PKC Function: Signal transducer. LAM of M. smegmatis Function: Ligand binding or carrier. (Ghosh et al., 1998) KanLM Function: Ligand binding or carrier. IL12 Function: Signal transducer. Interleukin 12 is a disulfide-linked heterodimer composed of a 40 kD cytokine receptor like subunit encoded by IL12B, and a 35 kD subunit encoded by IL12A. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development. This cytokine has been found to be important for sustaining a sufficient number of memory/effector Th1 cells to mediate long-term protection to an intracellular pathogen. Overexpression of this gene was observed in the central nervous system of patients with multiple sclerosis (MS), suggesting a role of this cytokine in the pathogenesis of the disease. The promoter polymorphism of this gene has been reported to be associated with the severity of atopic and non-atopic asthma in children. LMs Function: Ligand binding or carrier. (Dao et al., 2004) PILAM Function: Other. (Dao et al., 2004) PI-3K Function: Signal transducer. BAD Function: Signal transducer. The protein encoded by this gene is a member of the BCL-2 family. BCL-2 family members are known to be regulators of programmed cell death. This protein positively regulates cell apoptosis by forming heterodimers with BCL-xL and BCL-2, and reversing their death repressor activity. Proapoptotic activity of this protein is regulated through its phosphorylation. Protein kinases AKT and MAP kinase, as well as protein phosphatase calcineurin were found to be involved in the regulation of this protein. Alternative splicing of this gene results in two transcript variants which encode the same isoform. calcium uptake in cells Function: Signal transducer. (Rojas et al., 2000) ManLAM Function: Other. (Rojas et al., 2000) IL1B Function: Signal transducer. The protein encoded by this gene is a member of the interleukin 1 cytokine family. This cytokine is produced by activated macrophages as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE). This cytokine is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis. The induction of cyclooxygenase-2 (PTGS2/COX2) by this cytokine in the central nervous system (CNS) is found to contribute to inflammatory pain hypersensitivity. This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. CASP8 Function: Chaperone. This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. TLR2 Function: Signal transducer. p19 Function: Other. (López et al., 2003)(Ciaramella et al., 2000)(Ciaramella et al., 2004) BCL2 Function: Signal transducer. This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Two transcript variants, produced by alternate splicing, differ in their C-terminal ends. mycolic acid Function: Other. (Nuzzo et al., 2002) tuberculostearic acid Function: Other. apoptosis Function: Other. Cord Factors Function: Infection. Cord Factors. Toxic glycolipids composed of trehalose dimycolate derivatives. They are produced by MYCOBACTERIUM TUBERCULOSIS and other species of MYCOBACTERIUM. They induce cellular dysfunction in animals. BCL2L1 Function: Signal transducer. The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The proteins encoded by this gene are located at the outer mitochondrial membrane, and have been shown to regulate outer mitochondrial membrane channel (VDAC) opening. VDAC regulates mitochondrial membrane potential, and thus controls the production of reactive oxygen species and release of cytochrome C by mitochondria, both of which are the potent inducers of cell apoptosis. Two alternatively spliced transcript variants, which encode distinct isoforms, have been reported. The longer isoform acts as an apoptotic inhibitor and the shorter form acts as an apoptotic activator. Bax Function: Signal transducer. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. Multiple alternatively spliced transcript variants, which encode different isoforms, have been reported for this gene. cytochrome C Function: Other. This gene encodes cytochrome c, a component of the electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the b-c1 complex and transfers electrons to the cytochrome oxidase complex. Cytochrome c is also involved in initiation of apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor which activates the apoptotic initiator procaspase 9. Many cytochrome c pseudogenes exist, scattered throughout the human genome. MCL1 Function: Chaperone. The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. The longer gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene product (isoform 2) promotes apoptosis and is death-inducing. Mn superoxide dismutase Function: Enzyme. Bcl-w Function: Other. CASP3 Function: Enzyme. This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 6, 7 and 9, and the protein itself is processed by caspases 8, 9 and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer's disease. Alternative splicing of this gene results in two transcript variants that encode the same protein. CASP10 Function: Enzyme. This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene are associated with apoptosis defects seen in type II autoimmune lymphoproliferative syndrome. Three alternatively spliced transcript variants encoding different isoforms have been described for this gene. CASP9 Function: Enzyme. This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspase APAF1; this step is thought to be one of the earliest in the caspase activation cascade. Alternative splicing results in two transcript variants which encode different isoforms. M. bovis bacillus Calmette-Guérin (BCG) Function: Other. M. tuberculosis H37Rv Function: Other. virulent wild-type M. tuberculosis M. tuberculosis H37Ra Function: Other. attenuated M. tuberculosis (Riendeau and Kornfeld, 2003)