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1.C.54 The Shiga Toxin B Chain (ST-B) Family

The Shiga toxins I and II of E. coli are of the A-B type (like diphtheria toxin TC# 1.C.7)) and the Botulinum and Tetanus toxins (TC# 1.C.8). The intact toxins consist of one A chain (StxA) and 5 B chains (StxB). The five subunits (or B chains) bind glycolipids in the host eukaryotic cell membrane and form a pore that transports the enzymatic A-subunit into the cell. The A subunit is a glycosylase that catalyzes cleavage of a unique site in the 28S rRNA. Shiga toxins are also called verotoxins. They are encoded on the genomes of E. coli resident prophages of the lambda phage family.

A specific protein kinase C (PKC) isozyme, PKCδ, regulates the intracellular transport of the glycolipid-binding Shiga Toxin (Stx), which utilizes the retrograde pathway to intoxicate cells. Upon binding to cells, Stx was shown to specifically activate PKCδ. PKCδ, selectively regulates the endosome-to-Golgi transport of StxB. Upon inhibition or knockdown of PKCδ, StxB molecules colocalize less with giantin and more with EEA1, indicating that the molecules accumulate in endosomes, unable to reach the Golgi complex. The inhibition of Golgi transport reduces the toxic effect, demonstrating that transport of Stx to the cytosol is dependent on PKCδ activity (Torgersen et al., 2007).

Clathrin seems to be dispensable for some endocytic processes and, in several instances, no cytosolic coat protein complexes are detected at sites of membrane invagination. Hence, new principles must be invoked to account for the mechanical force driving membrane shape changes. Romer et al. (Romer et al. 2007) found that the Gb3 (glycolipid)-binding β-subunit of bacterial Shiga toxin induces narrow tubular membrane invaginations in human and mouse cells as well as in model membranes. In cells, tubule occurrence increases on energy depletion and inhibition of dynamin or actin functions. They suggest that the β-subunit induces lipid reorganization that favours negative membrane curvature. This, in turn, drives the formation of inward membrane tubules. The lateral growth of β-subunit-Gb3 microdomains may be limited by the invagination process which is regulated by membrane tension. The physical principles underlying this basic cargo-induced membrane uptake may be relevant to other internalization processes, creating a rationale for conceptualizing the perplexing diversity of endocytic routes (Romer et al., 2007).

 

The transport reaction catalyzed by ST-B proteins is:

 

 

ST-A (out) → ST-A (in)

 

References associated with 1.C.54 family:

Römer, W., L. Berland, V. Chambon, K. Gaus, B. Windschiegl, D. Tenza, M.R. Aly, V. Fraisier, J.C. Florent, D. Perrais, C. Lamaze, G. Raposo, C. Steinem, P. Sens, P. Bassereau, and L. Johannes. (2007). Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature 450: 670-675. 18046403
Torgersen, M.L., S. Wälchli, S. Grimmer, S.S. Skånland, and K. Sandvig. (2007). Protein kinase Cdelta is activated by Shiga toxin and regulates its transport. J. Biol. Chem. 282: 16317-16328. 17403690
Wagner, P.L., M.N. Neely, X. Zhang, D.W.K. Acheson, M.K. Waldor and D.I. Friedman (2001). Role for a phage promoter in shiga toxin 2 expression from a pathogenic Escherichia coli strain. J. Bacteriol. 183: 2081-2085.

Torgersen, L., S. Walchli, S. Grimmer, S.S. Skanland, and K. Sandvig (2007). Protein Kinase Cδ Is Activated by Shiga Toxin and Regulates Its Transport. Journal of Biological Chemistry. Vol 282, Number 22: 16317.

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