TCDB is operated by the Saier Lab Bioinformatics Group

1.C.41 The Tripartite Haemolysin BL (HBL) Family

The HBL family includes a tipartite haemolysin from Bacillus cereus (Beecher and Wong 2000). The three components are homologous but distantly related to each other. They are called HBL component B, HBL component L1 and HBL component L2. The toxin forms pores and has also been called the enterotoxic, necrotizing, vascular, permeability toxin, a likely virulence factor of B. cereus diarrheal food poisoning and necrotic infections (Sastalla et al. 2013). Two distinct sets of all three HBL components have been isolated from a single B. cereus isolate, MGBC145. Both exhibit haemolytic and vascular permeability activities, and the homologues could function interchangeably. In addition to B. cereus, a homologue, called Haemolysin YhlA has been isolated and characterized from Edwardsiella tarda (Chen et al. 1996).

Inflammasomes are important for host defence against pathogens and homeostasis with commensal microbes. Fox et al. 2020 showed non-haemolytic enterotoxin (NHE) from the human foodborne pathogen, Bacillus cereus, is an activator of the NLRP3 inflammasome and pyroptosis. NHE is a non-redundant toxin to haemolysin BL (HBL) despite having a similar mechanism of action. Via a putative TMS, subunit C of NHE initiates binding to the plasma membrane, leading to the recruitment of subunits B and A, thus forming a tripartite lytic pore that allows efflux of potassium. NHE mediates killing of cells from multiple lineages and hosts, highlighting a versatile functional repertoire in different host species. These data indicate that NHE and HBL operate synergistically to induce inflammation and show that multiple virulence factors from the same pathogen with conserved function and mechanism of action can be exploited for sensing by a single inflammasome (Fox et al. 2020).

The generalized transport reaction catalyzed by HBL is:

Solutes (in) ⇌ solutes (out)

References associated with 1.C.41 family:

Beecher, D.J. and A.C. Wong. (2000). Tripartite haemolysin BL: isolation and characterization of two distinct homologous sets of components from a single Bacillus cereus isolate. Microbiology 146(Pt6): 1371-1380. 10846215
Bräuning, B., E. Bertosin, F. Praetorius, C. Ihling, A. Schatt, A. Adler, K. Richter, A. Sinz, H. Dietz, and M. Groll. (2018). Structure and mechanism of the two-component α-helical pore-forming toxin YaxAB. Nat Commun 9: 1806. 29728606
Buchacher, T., A. Digruber, M. Kanzler, G. Del Favero, and M. Ehling-Schulz. (2023). Bacillus cereus extracellular vesicles act as shuttles for biologically active multicomponent enterotoxins. Cell Commun Signal 21: 112. 37189133
Chen, J.D., S.Y. Lai, and S.L. Huang. (1996). Molecular cloning, characterization, and sequencing of the hemolysin gene from Edwardsiella tarda. Arch. Microbiol. 165: 9-17. 8639026
Dementiev, A., J. Board, A. Sitaram, T. Hey, M.S. Kelker, X. Xu, Y. Hu, C. Vidal-Quist, V. Chikwana, S. Griffin, D. McCaskill, N.X. Wang, S.C. Hung, M.K. Chan, M.M. Lee, J. Hughes, A. Wegener, R.V. Aroian, K.E. Narva, and C. Berry. (2016). The pesticidal Cry6Aa toxin from Bacillus thuringiensis is structurally similar to HlyE-family alpha pore-forming toxins. BMC Biol 14: 71. 27576487
Fagerlund, A., T. Lindbäck, A.K. Storset, P.E. Granum, and S.P. Hardy. (2008). Bacillus cereus Nhe is a pore-forming toxin with structural and functional properties similar to the Cl- yA (HlyE, SheA) family of haemolysins, able to induce osmotic lysis in epithelia. Microbiology 154: 693-704. 18310016
Fagerlund, A., T. Lindbäck, and P.E. Granum. (2010). Bacillus cereus cytotoxins Hbl, Nhe and CytK are secreted via the Sec translocation pathway. BMC Microbiol 10: 304. 21118484
Fox, D., A. Mathur, Y. Xue, Y. Liu, W.H. Tan, S. Feng, A. Pandey, C. Ngo, J.A. Hayward, I.I. Atmosukarto, J.D. Price, M.D. Johnson, N. Jessberger, A.A.B. Robertson, G. Burgio, D.C. Tscharke, E.M. Fox, D.L. Leyton, N.O. Kaakoush, E. Märtlbauer, S.H. Leppla, and S.M. Man. (2020). Bacillus cereus non-haemolytic enterotoxin activates the NLRP3 inflammasome. Nat Commun 11: 760. 32029733
Gupta, L.K., J. Molla, and A.A. Prabhu. (2023). Story of Pore-Forming Proteins from Deadly Disease-Causing Agents to Modern Applications with Evolutionary Significance. Mol Biotechnol. [Epub: Ahead of Print] 37294530
Huang, J., Z. Guan, L. Wan, T. Zou, and M. Sun. (2016). Crystal structure of Cry6Aa: A novel nematicidal ClyA-type α-pore-forming toxin from Bacillus thuringiensis. Biochem. Biophys. Res. Commun. 478: 307-313. 27381865
Kopanja, L., Z. Kovacevic, M. Tadic, M.C. Žužek, M. Vrecl, and R. Frangež. (2018). Confocal micrographs: automated segmentation and quantitative shape analysis of neuronal cells treated with ostreolysin A/pleurotolysin B pore-forming complex. Histochem Cell Biol 150: 93-102. 29687242
Liu, X., S. Ding, P. Shi, R. Dietrich, E. Märtlbauer, and K. Zhu. (2016). Non-haemolytic enterotoxin (Nhe) of Bacillus cereus induces apoptosis in Vero cells. Cell Microbiol. [Epub: Ahead of Print] 27762484
Nadeem, A., A. Berg, H. Pace, A. Alam, E. Toh, J. Ådén, N. Zlatkov, S.L. Myint, K. Persson, G. Gröbner, A. Sjöstedt, M. Bally, J. Barandun, B.E. Uhlin, and S.N. Wai. (2022). Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from. Elife 11:. 35131030
Sastalla, I., R. Fattah, N. Coppage, P. Nandy, D. Crown, A.P. Pomerantsev, and S.H. Leppla. (2013). The Bacillus cereus Hbl and Nhe tripartite enterotoxin components assemble sequentially on the surface of target cells and are not interchangeable. PLoS One 8: e76955. 24204713
Schubert, E., I.R. Vetter, D. Prumbaum, P.A. Penczek, and S. Raunser. (2018). Membrane insertion of α-xenorhabdolysin in near-atomic detail. Elife 7:. 30010541
Vigneux, F., R. Zumbihl, G. Jubelin, C. Ribeiro, J. Poncet, S. Baghdiguian, A. Givaudan, and M. Brehélin. (2007). The xaxAB genes encoding a new apoptotic toxin from the insect pathogen Xenorhabdus nematophila are present in plant and human pathogens. J. Biol. Chem. 282: 9571-9580. 17229739
Wagner, N.J., C.P. Lin, L.B. Borst, and V.L. Miller. (2013). YaxAB, a Yersinia enterocolitica pore-forming toxin regulated by RovA. Infect. Immun. 81: 4208-4219. 24002058
Zhu, K., A. Didier, R. Dietrich, U. Heilkenbrinker, E. Waltenberger, N. Jessberger, E. Märtlbauer, and R. Benz. (2015). Formation of small transmembrane pores: An intermediate stage on the way to Bacillus cereus non-hemolytic enterotoxin (Nhe) full pores in the absence of NheA. Biochem. Biophys. Res. Commun. [Epub: Ahead of Print] 26654951