|Year : 2018 | Volume
| Issue : 2 | Page : 100-105
A review on the C-terminal domain of channel protein with necrosis-inducing toxin as a novel necrotizing toxin of Mycobacterium tuberculosis
Poopak Farnia1, Tayebeh Farhadi2, Parissa Farnia2, Jalaledin Ghanavi2, Ali Akbar Velayati2
1 Department of Biotechnology, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran
|Date of Web Publication||14-Jun-2018|
Dr. Tayebeh Farhadi
Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, P. O. Box 19569, Tehran
Source of Support: None, Conflict of Interest: None
Tuberculosis is a highly infectious illness that has been considered a worldwide health danger. Existence inside macrophages is a main characteristic of Mycobacterium tuberculosis virulence and essential to make a perdurable infection in the human body. Recently, a pivotal cytotoxicity determinant of M. tuberculosis in macrophages was discovered and named channel protein with necrosis-inducing toxin (CpnT). CpnT includes an N-terminal channel domain and a C-terminal domain (CTD). The CTD is a secreted toxin and can induce a necrotizing process in the macrophages. The CTD has strong nicotinamide adenine dinucleotide (NAD+)-glycohydrolase activity that empties NAD+ reservoirs of cells, resulting in human cell necrosis. In this study, the structural and functional properties of the CTD were reviewed. Besides, to predict local similarity between the CTD and other protein sequences and infer the functional and evolutionary relationships, the Basic Local Alignment Search Tool was used. Several protein sequences of the Mycobacterium showed >50% similarity to the CTD, indicating species specificity of the CTD. However, some prokaryotic and eukaryotic sequences showed 20%–45% similarity to the CTD, indicating that the CTD belongs to an uncharacterized protein family including nonbacterial proteins.
Keywords: Macrophages, Mycobacterium tuberculosis, necrosis-inducing toxin
|How to cite this article:|
Farnia P, Farhadi T, Farnia P, Ghanavi J, Velayati AA. A review on the C-terminal domain of channel protein with necrosis-inducing toxin as a novel necrotizing toxin of Mycobacterium tuberculosis. Biomed Biotechnol Res J 2018;2:100-5
|How to cite this URL:|
Farnia P, Farhadi T, Farnia P, Ghanavi J, Velayati AA. A review on the C-terminal domain of channel protein with necrosis-inducing toxin as a novel necrotizing toxin of Mycobacterium tuberculosis. Biomed Biotechnol Res J [serial online] 2018 [cited 2019 May 24];2:100-5. Available from: http://www.bmbtrj.org/text.asp?2018/2/2/100/234462
| Introduction|| |
Tuberculosis is a serious infectious illness that has been considered a worldwide health danger. Existence inside macrophages is a main characteristic of Mycobacterium tuberculosis virulence and is essential to make a perdurable infection in the human body.,,,,, The conflict between M. tuberculosis and host immunity responses is crucial to determine the fate of infected macrophages and regulate the consequence of the infection.,, To escape the immune system and distribute, M. tuberculosis suppresses the human cell apoptosis and causes necrosis of the macrophages.,
To manage the time and mechanism of human cell necrosis, many pathogenic bacteria utilize toxic proteins to destroy host cells and escape immune system. The absence of homolog proteins of identified bacterial toxins in the M. tuberculosis and the failure to separate secreted toxic proteins resulted in a general opinion that M. tuberculosis does not express such typical pathogenic macromolecules.,, However, this hypothesis was challenged by the finding of a channel protein with necrosis-inducing toxin (CpnT) as a pivotal toxicity determinant of M. tuberculosis in host cells.
In 2014, Danilchanka et al. showed that the protein Rv3903c of M. tuberculosis is essential for persistence and toxicity of the pathogen in macrophages. Rv3903c contains a secreted toxic C-terminal domain (CTD) and an N-terminal channel domain (NTD). Hence, Rv3903c was named CpnT. To uptake of nutrients across the outer membrane, the NTD of the CpnT (CpnTNTD) is useful, and to induce necrosis in eukaryotic cells, the CpnTNTD is pivotal. Consequently, CpnT was demonstrated to have a dual activity in the stimulation of host cell death as well as uptake the nutrients by M. tuberculosis. The CTD of the CpnT (CpnTCTD) was also named tuberculosis-necrotizing toxin (TNT).
The outer membrane channel protein with necrosis-inducing toxin of Mycobacterium tuberculosis
The outer membrane has a key role for survival of bacteria such as M. tuberculosis under severe conditions of the human body., Nevertheless, the proteins that make the outer membrane capable to do its functions are vastly unknown. The roles of the recognized outer membrane proteins of M. tuberculosis have not been verified by phenotypes of the corresponding mutants. However, deletion mutation of a CpnTNTD of the bacterium resulted in deficiency in the channel-forming activity and small molecule uptake representing the protein role as an outer membrane protein.
Architecture and topology of channel protein with necrosis-inducing toxin
MspA is only known mycobacterial porin and has a secretion (Sec) signal sequence., Such classical Sec signal sequence has not been detected in the CpnT; hence, its organization is abnormal for a channel-making protein., Moreover, CpnT has at least two domains that make it abnormally big as a porin. To construct a channel in the outer membrane of M. tuberculosis, the NTD of the protein (aa 1–443) is necessary. Homologs of the NTD are existent in the sequenced genome mycobacteria.
The architecture of CpnT is similar to toxic auto-transporters of Gram-negative bacteria. Toxic auto-transporters assist translocation of a toxic passenger domain.,,,, Moreover, the oligomerization is necessary for functionality of the toxic auto-transporters as well as CpnT. Consequently, CpnT might be considered the first auto-transporter-like protein of M. tuberculosis. Nevertheless, auto-transporters of the bacteria depend on the β-barrel association mechanism to assemble and integrate the outer membrane., This mechanism is likely different in CpnT.,
The biological activity of channel protein with necrosis-inducing toxin
Discovering the toxic CpnTCTD (or TNT) challenged the hypothesis that M. tuberculosis may do not make toxins., A model was suggested for the biological function of CpnT as follows: following phagocytosis of M. tuberculosis, phagosomal and cytosolic compositions of macrophages are mixed via ESX-1-dependent permeabilization., CpnT is inserted into the bacterial outer membrane and cleaved to the CTD and NTD by proteolytic enzymes. The NTD assists to uptake of hydrophilic compounds including glycerol and ampicillin in the outer membrane. The toxic CTD (residues 651–846) is discharged from the cell surface of M. tuberculosis to initiate necrotizing of the macrophages.M. tuberculosis discharges from the endosome and finally the infected macrophage after the necrotic fragmentation of the macrophages.,
In M. tuberculosis, CpnT is a double-functional protein to increase outer membrane compounds passing via its channel-forming NTD and transport the toxic CTD to the bacterial surface.
Phylogeny and structure of C-terminal domain of the channel protein with necrosis-inducing toxin
Employing bioinformatic analysis, it was shown that the amino acids 720–846 of the CTD belong to family DUF4237 of proteins, including near 200 fungal and bacterial proteins. Moreover, in other virulence mycobacteria such as Mycobacterium marinum, homolog proteins of CpnT contain same N terminus but dissimilar C terminus. These conclusions proposed that CpnT has two domains including the N terminus typical in mycobacteria and the species-particular C end.
In this study, to predict local similarity between the CTD and other protein sequences and infer the functional and evolutionary relations, the Basic Local Alignment Search Tool (BLAST) was used. The sequence of the CpnTCTD was retrieved from UniProtKB (http://www.uniprot.org/), and the BLAST was performed to search similar protein sequences. The BLAST detects fragments of local similarity among sequences. It may be utilized to understand practical and evolutionary associations among sequences and detect members of protein classes (https://blast.ncbi.nlm.nih.gov/Blast.cgi).
The results are represented in [Table 1]. Considering to [Table 1], protein sequences of some species in the genus Mycobacterium have 99.5%–100% similarity to the CDT and a number of protein sequences in this genus show 50%–65% similarity to the CTD. The observation that the protein sequences with >50% similarity to the CTD belong to the Mycobacterium indicates the species specificity of the CTD. Except Mycobacterium abscessus (with 50%–65% similarity), sequences of fast-growing mycobacteria are not similar to the CTD sequence.
|Table 1: Similarity between the protein sequences deposited in the UniProtKB and the C-terminal domain sequence|
Click here to view
Considering to the results [Table 1], the protein sequences with 20%–45% similarity to the CTD belong to different organisms including bacteria (both mycobacteria and nonmycobacteria), fungi, and eukaryotes (protozoa, plants, and animals). Such similarity between the CTD and prokaryotic/eukaryotic sequences is consistent with the hypothesis that the CTD belongs to the uncharacterized protein family including nonbacterial proteins.
Structural investigation of the CTD has revealed that the toxin contains two parts including a “thumb” (amino acids 648–736) and a “palm-domain” (amino acids 747–846), in which the thumb wraps around the palm domain. [Figure 1]a and [Figure 1]b shows the structure of the CTD (protein data bank [PDB] ID: 4QLP). [Figure 1]a displays cartoon representation of the CTD with the thumb and the palm domains, colored in blue and green, respectively. [Figure 1]b represents surface representation of the CTD. The structures were visualized using PyMOL tool.
|Figure 1: The structure of C-terminal domain (protein data bank ID: 4QLP). (a) Cartoon representation of the C-terminal domain. (b) Surface representation of the C-terminal domain|
Click here to view
C-terminal domain of the channel protein with necrosis-inducing toxin is toxic in prokaryotic and eukaryotic cells
The fragment CpnTCTD comprises an independent domain.In vitro experiments on mammalian cell lines showed that CpnTCTD is toxic in different cell types. This proposed that CpnTCTD does not kill only the specific eukaryotic cell lines. Toxicity of recombinant CpnTCTD in all investigated prokaryotic and eukaryotic cells has been illustrated indicating that the CTD may have a common prokaryotic and eukaryotic cellular target.
Mechanism of C-terminal domain of the channel protein with necrosis-inducing toxin-caused necrosis
It is demonstrated that the CTD has strong nicotinamide adenine dinucleotide (NAD +)-glycohydrolase activity that empties cellular NAD + reservoirs and leads to human cell death. NAD + is both a substrate for NAD +-consuming enzymes and an essential coenzyme for hydride-transfer enzymes. The hydride-transfer enzymes involve in many redox reactions, and NAD +-consuming enzymes have pivotal roles in transcriptional control., NAD + hydrolysis may reveal CpnTCTD cytotoxicity since exhaustion of cytoplasmic NAD + adjusts ATP production via glycolysis and results in necrosis., Chromatography studies disclosed that CpnTCTD is a glycohydrolase that powerfully splits NAD + into an ADP-ribose and the nicotinamide. All identified NAD +-degrading enzymes discharge nicotinamide and a second component such as the ADP-ribose or cyclic ADP-ribose.
The C-terminal domain-immunity factor for tuberculosis-necrotizing toxin complex
In 2015, an endogenous protein of M. tuberculosis was discovered to behave as an anti-toxin for CpnTCTD to inhibit the bacterial self-poisoning. This anti-toxin was named immunity factor for TNT (IFT) and its three-dimensional (3D) structure in complex with the CTD was determined. In the structure, a novel NAD +-binding module different from known NAD +-utilizing toxins was detected. IFT has a globular structure that includes a helical and a β-rich domain.
[Figure 2]a and [Figure 2]b shows 3D structure of the CTD-IFT complex (PDB ID: 4QLP). [Figure 2]a shows the cartoon representation of the CTD (in green) interacting to IFT (in yellow). [Figure 2]b displays mesh representation of the CTD-IFT complex surfaces.
|Figure 2: Three dimensional structure of the C-terminal domain-immunity factor for tuberculosis-necrotizing toxin complex (protein data bank ID: 4QLP). (a) The cartoon representation of the C-terminal domain (in green) bound to immunity factor for tuberculosis necrotizing toxin (in yellow). (b) Mesh representation of the C-terminal domain (in green) bound to immunity factor for tuberculosis-necrotizing toxin (in yellow)|
Click here to view
The putative nicotinamide adenine dinucleotide +-binding site on the C-terminal domain
An extensive search for identical structures of the CTD failed to gain important achievements. Hence, the CTD seems to have no complete sequence likeness to proteins with identified function. However, using a restraint-based structural alignment, a similarity between the architecture of the NAD +-binding site of the CTD with the SPN-glycohydrolase domain  as well as the ribosyltransferase domain of the diphtheria and cholera toxins was disclosed., Remarkable dissimilarity is that the CTD core consists of only six β-strands as compared to seven discovered in identified NAD +-utilizing toxins., Moreover, the CTD core is meaningfully smaller than the NAD +-using toxins. Examination of the amino acids nearby the NAD +-binding site recognized R757, Y765, and Q822 as amino acids likely associated with NAD + attachment and degradation. The Q822 is remarkably conserved among the CTD homologs.
C-terminal domain-related nicotinamide adenine dinucleotide + depletion induces cell necrotizing
To evaluate whether NAD + exhaustion via the CTD results in cell death, researchers transfected the macrophages with plasmids expressing wild- or noncatalytic-mutant ctd genes. The wild CTD destroyed more than 50% of the transfected macrophages, but the noncatalytic CTD mutants entirely lost toxicity. These findings demonstrated that macrophage necrotizing is a result of the NAD +-glycohydrolase by CTD. It is also demonstrated that NAD + depletion in infected macrophages essentially relates to the enzymatic activity of CpnTCTD. Furthermore, the NAD + precursor supplementation examinations indicated that the NAD + hydrolysis has a direct role in the toxicity of CTD and can be the key toxicity mechanism of M. tuberculosis in macrophages.
Mechanism of C-terminal domain entrance to the macrophage cytosol
Generally, various microbial toxins enter into host cells by receptor-mediated phagocytosis.,, Putative cellular uptake pathways for CTD were examined. Results showed that by adding the purified CTD to macrophages, macrophage cell death was not induced representing that CTD does not have a membrane passing region. Moreover, incorporated latex beads with the CTD did not result in host–cell disruption, signifying that CTD itself is not able to exit from the phagosome.
M. tuberculosis may secrete the CTD to the cytoplasm of the infected cells, while the pathogens are enclosed to the endosome. Interestingly, CTD is not uniformly dispersed in the cytoplasm of infected cells, but rather displays dotted localization, probably from corporation to cellular organelles.
Entrance to the host cell cytoplasm, but not secretion of the CTD by M. tuberculosis, entirely relates to the ESX-1-secreting system conforming to previous recommendations that the ESX-1 complex is necessary for M. tuberculosis toxicity  and the endosomal membrane is punctured in an ESX-1 relative way.
NoodleTree genome displays tuberculosis-related activity
The mycobacteriophage, NoodleTree, was discovered in 2016 from soil in Texas. Isolation, amplification, and characterization of the bacteriophage relieved that NoodleTree is a unique Myoviridae bacteriophage that specifically infects Mycobacterium smegmatis. The bacteria M. smegmatis and M. tuberculosis have 2000 homologous genes and the same peculiar wall structures and therefore may be genetically similar.
Genomic analysis of NoodleTree relieved that the phage genome is a member of C1 phage cluster with a length of over 150 kilobase pair. However, a large series of genes existing in other C1 phage clusters is absent from NoodleTree genome. The absence of these genes may be related to the phage efficacy and specificity to its unique bacteria including M. smegmatis and M. tuberculosis.
The genomic protein 8 (GP8) is only found in NoodleTree and nine other C1 phage. The gp8 is homolog of both TNT and IFT and possibly codes for a protein with M. tuberculosis functionality. In majority of C1 phages, GP8 may overlap with TNT functionally and have high sequence similarity with M. tuberculosis IFT and TNT. However, similarity between NoodleTree GP8 and the toxin module (TNT and IFT) has been predicted to be <40%.,,,
Via general transduction, phages may mediate genetic transfer of virulence and consequently increase the levels of infection and number of possible bacterial hosts. If the toxin activity of TNT is detected in a novel host with no former infectious ability, then it may be explained by the ability of NoodleTree to transfer virulence into the host.
Analyzing the NoodleTree genome may result the finding of genes that specially target structural and functional aspects of M. smegmatis and therefore M. tuberculosis. The precise identification of such regions of interest in the bacteriophage genome and the overall biological processes of both the phage and target bacteria can be useful to employ in various applications including phage therapy, prophylaxis treatment, and oncolytic viral treatments.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Velayati AA, Farnia P, Masjedi MR. Totally drug-resistant tuberculosis (TDR-TB): A debate on global health communities. Int J Mycobacteriol 2013;2:71-2. [Full text]
Velayati AA, Farnia P, Masjedi MR. Latent tuberculosis (TB) bacilli: Yes or no to preventive chemotherapy. Int J Mycobacteriol 2012;1:1-2. [Full text]
Russell DG, Barry CE 3rd
, Flynn JL. Tuberculosis: What we don't know can, and does, hurt us. Science 2010;328:852-6.
Velayati AA, Farnia P, Hoffner S. Drug-resistant Mycobacterium tuberculosis
: Epidemiology and role of morphological alterations. J Glob Antimicrob Resist 2018;12:192-6.
Velayati AA, Farnia P. Division-cycle in Mycobacterium tuberculosis
. Int J Mycobacteriol 2012;1:111-7. [Full text]
Farnia P, Velayati AA, Mollaei S, Ghanavi J. Modified rifampin nanoparticles: Increased solubility with slow release rate. Int J Mycobacteriol 2017;6:171-6.
] [Full text]
Velayati AA, Farnia P, Mozafari M, Sheikholeslami MF, Karahrudi MA, Tabarsi P, et al.
High prevalence of rifampin-monoresistant tuberculosis: A retrospective analysis among Iranian pulmonary tuberculosis patients. Am J Trop Med Hyg 2014;90:99-105.
Behar SM, Divangahi M, Remold HG. Evasion of innate immunity by Mycobacterium tuberculosis
: Is death an exit strategy? Nat Rev Microbiol 2010;8:668-74.
Baghaei P, Tabarsi P, Jabehdari S, Marjani M, Moniri A, Farnia P, et al.
HIV and tuberculosis trends and survival of coinfection in a referral center in Tehran: A 12-year study. Int J Mycobacteriol 2016;5 Suppl 1:S16-7.
Saif S, Farnia P, Ghamari E, Ghanavi J, Farnia P, Velayati AA. Comparison of TNF-α promoter region with TNF receptor 1 and 2 (TNFR1 and TNFR2) in susceptibility to pulmonary tuberculosis; by PCR-RFLP. Biomed Res 2017;28:8085-90.
Behar SM, Martin CJ, Booty MG, Nishimura T, Zhao X, Gan HX, et al.
Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis
. Mucosal Immunol 2011;4:279-87.
Divangahi M, Behar SM, Remold H. Dying to live: How the death modality of the infected macrophage affects immunity to tuberculosis. Adv Exp Med Biol 2013;783:103-20.
Henkel JS, Baldwin MR, Barbieri JT. Toxins from bacteria. EXS 2010;100:1-29.
Gordon SV, Bottai D, Simeone R, Stinear TP, Brosch R. Pathogenicity in the tubercle bacillus: Molecular and evolutionary determinants. Bioessays 2009;31:378-88.
Mukhopadhyay S, Nair S, Ghosh S. Pathogenesis in tuberculosis: Transcriptomic approaches to unraveling virulence mechanisms and finding new drug targets. FEMS Microbiol Rev 2012;36:463-85.
Forrellad MA, Klepp LI, Gioffré A, Sabio y García J, Morbidoni HR, de la Paz Santangelo M, et al.
Virulence factors of the Mycobacterium tuberculosis
complex. Virulence 2013;4:3-66.
Danilchanka O, Sun J, Pavlenok M, Maueröder C, Speer A, Siroy A, et al.
An outer membrane channel protein of Mycobacterium tuberculosis
with exotoxin activity. Proc Natl Acad Sci U S A 2014;111:6750-5.
Sun J, Siroy A, Lokareddy RK, Speer A, Doornbos KS, Cingolani G, et al.
The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD. Nat Struct Mol Biol 2015;22:672-8.
Velayati AA, Farnia P, Masjedi MR. Pili in totally drug resistant Mycobacterium tuberculosis
(TDR-TB). Int J Mycobacteriol 2012;1:57-8. [Full text]
Barry CE 3rd
. Interpreting cell wall 'virulence factors' of Mycobacterium tuberculosis
. Trends Microbiol 2001;9:237-41.
Niederweis M, Danilchanka O, Huff J, Hoffmann C, Engelhardt H. Mycobacterial outer membranes: In search of proteins. Trends Microbiol 2010;18:109-16.
de Keyzer J, van der Does C, Driessen AJ. The bacterial translocase: A dynamic protein channel complex. Cell Mol Life Sci 2003;60:2034-52.
Niederweis M, Ehrt S, Heinz C, Klöcker U, Karosi S, Swiderek KM, et al.
Cloning of the mspA gene encoding a porin from Mycobacterium smegmatis
. Mol Microbiol 1999;33:933-45.
Oberhettinger P, Schütz M, Leo JC, Heinz N, Berger J, Autenrieth IB, et al.
Intimin and invasin export their C-terminus to the bacterial cell surface using an inverse mechanism compared to classical autotransport. PLoS One 2012;7:e47069.
Dautin N, Bernstein HD. Protein secretion in gram-negative bacteria via the autotransporter pathway. Annu Rev Microbiol 2007;61:89-112.
Saurí A, Oreshkova N, Soprova Z, Jong WS, Sani M, Peters PJ, et al.
Autotransporter β-domains have a specific function in protein secretion beyond outer-membrane targeting. J Mol Biol 2011;412:553-67.
Leyton DL, Rossiter AE, Henderson IR. From self sufficiency to dependence: Mechanisms and factors important for autotransporter biogenesis. Nat Rev Microbiol 2012;10:213-25.
Benz I, Schmidt MA. Structures and functions of autotransporter proteins in microbial pathogens. Int J Med Microbiol 2011;301:461-8.
Selkrig J, Mosbahi K, Webb CT, Belousoff MJ, Perry AJ, Wells TJ, et al.
Discovery of an archetypal protein transport system in bacterial outer membranes. Nat Struct Mol Biol 2012;19:506-10, S1.
Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS. Mycobacterium tuberculosis
activates the DNA-dependent cytosolic surveillance pathway within macrophages. Cell Host Microbe 2012;11:469-80.
Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, et al.
Phagosomal rupture by Mycobacterium tuberculosis
results in toxicity and host cell death. PLoS Pathog 2012;8:e1002507.
van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, et al. M. tuberculosis
and M. leprae
translocate from the phagolysosome to the cytosol in myeloid cells. Cell 2007;129:1287-98.
Welin A, Lerm M. Inside or outside the phagosome? The controversy of the intracellular localization of Mycobacterium tuberculosis
. Tuberculosis (Edinb) 2012;92:113-20.
Belenky P, Bogan KL, Brenner C. NAD+metabolism in health and disease. Trends Biochem Sci 2007;32:12-9.
Lin SJ, Guarente L. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 2003;15:241-6.
Du L, Zhang X, Han YY, Burke NA, Kochanek PM, Watkins SC, et al.
Intra-mitochondrial poly (ADP-ribosylation) contributes to NAD+depletion and cell death induced by oxidative stress. J Biol Chem 2003;278:18426-33.
Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev 2006;20:1-5.
Smith CL, Ghosh J, Elam JS, Pinkner JS, Hultgren SJ, Caparon MG, et al.
Structural basis of Streptococcus pyogenes
immunity to its NAD+ glycohydrolase toxin. Structure 2011;19:192-202.
Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, et al.
The crystal structure of diphtheria toxin. Nature 1992;357:216-22.
Zhang RG, Scott DL, Westbrook ML, Nance S, Spangler BD, Shipley GG, et al.
The three-dimensional crystal structure of cholera toxin. J Mol Biol 1995;251:563-73.
Fieldhouse RJ, Turgeon Z, White D, Merrill AR. Cholera – And anthrax-like toxins are among several new ADP-ribosyltransferases. PLoS Comput Biol 2010;6:e1001029.
Lord JM, Smith DC, Roberts LM. Toxin entry: How bacterial proteins get into mammalian cells. Cell Microbiol 1999;1:85-91.
Torgersen ML, Skretting G, van Deurs B, Sandvig K. Internalization of cholera toxin by different endocytic mechanisms. J Cell Sci 2001;114:3737-47.
Barth H, Aktories K. New insights into the mode of action of the actin ADP-ribosylating virulence factors Salmonella enterica
SpvB and Clostridium Botulinum
C2 toxin. Eur J Cell Biol 2011;90:944-50.
Butler RE, Brodin P, Jang J, Jang MS, Robertson BD, Gicquel B, et al.
The balance of apoptotic and necrotic cell death in Mycobacterium tuberculosis
infected macrophages is not dependent on bacterial virulence. PLoS One 2012;7:e47573.
Lee J, Repasy T, Papavinasasundaram K, Sassetti C, Kornfeld H. Mycobacterium tuberculosis
induces an atypical cell death mode to escape from infected macrophages. PLoS One 2011;6:e18367.
Int-Hout B, Flores L. Tuberculosis (TB) and NoodleTree: Verifying genetic sequence data and functionality of a generally transduced M. tuberculosis
toxin through a viral carrier. Biophys J 2018;114:666a.
Gondil VS, Chhibber S. Exploring potential of phage therapy for tuberculosis using model organism. Biomed Biotechnol Res J 2018;2:9-15. [Full text]
Jena L, Harinath BC. Anti-tuberculosis therapy: Urgency for new drugs and integrative approach. Biomed Biotechnol Res J 2018;2:16-9. [Full text]
Farhadi T. Advances in protein tertiary structure prediction: A review. Biomed Biotechnol Res J 2018;2:20-5. [Full text]
[Figure 1], [Figure 2]