Manganese Blocks Intracellular Trafficking of Shiga Toxin and Protects Against Shiga Toxicosis

Overview

Journal Science

Specialty Science

Date 2012 Jan 24

PMID 22267811

Citations 71

Authors

Somshuvra Mukhopadhyay

Adam D Linstedt

Affiliations

Soon will be listed here.

Abstract

Infections with Shiga toxin (STx)-producing bacteria cause more than a million deaths each year and have no definitive treatment. To exert its cytotoxic effect, STx invades cells through retrograde membrane trafficking, escaping the lysosomal degradative pathway. We found that the widely available metal manganese (Mn(2+)) blocked endosome-to-Golgi trafficking of STx and caused its degradation in lysosomes. Mn(2+) targeted the cycling Golgi protein GPP130, which STx bound in control cells during sorting into Golgi-directed endosomal tubules that bypass lysosomes. In tissue culture cells, treatment with Mn(2+) yielded a protection factor of 3800 against STx-induced cell death. Furthermore, mice injected with nontoxic doses of Mn(2+) were completely resistant to a lethal STx challenge. Thus, Mn(2+) may represent a low-cost therapeutic agent for the treatment of STx infections.

Citing Articles

Structural Basis for Antibody Neutralization of Pertussis Toxin.

Goldsmith J, Nguyen A, Wilen R, Wijagkanalan W, McLellan J, Maynard J bioRxiv. 2024; .

PMID: 39386618 PMC: 11463501. DOI: 10.1101/2024.09.23.614357.

Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation.

He N, Depta L, Rossetti C, Caramelle L, Cigler M, Bryce-Rogers H Nat Chem Biol. 2024; 21(2):203-214.

PMID: 38907112 DOI: 10.1038/s41589-024-01653-x.

Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

Tan X, Wang S, Xiao G, Wu C, Liu X, Zhou B J Clin Invest. 2024; 134(12).

PMID: 38662435 PMC: 11178546. DOI: 10.1172/JCI176355.

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists.

Hollingsworth L, Veeraraghavan P, Paulo J, Harper J bioRxiv. 2024; .

PMID: 38659763 PMC: 11042255. DOI: 10.1101/2024.04.19.590338.

Manganese regulation of COPII condensation controls circulating lipid homeostasis.

Wang X, Huang R, Wang Y, Zhou W, Hu Y, Yao Y Nat Cell Biol. 2023; 25(11):1650-1663.

PMID: 37884645 DOI: 10.1038/s41556-023-01260-3.

References

Suzuki H, Wada O . Role of liver lysosomes in uptake and biliary excretion of manganese in mice. Environ Res. 1981; 26(2):521-8. DOI: 10.1016/0013-9351(81)90227-9. View

Bujny M, Popoff V, Johannes L, Cullen P . The retromer component sorting nexin-1 is required for efficient retrograde transport of Shiga toxin from early endosome to the trans Golgi network. J Cell Sci. 2007; 120(Pt 12):2010-21. DOI: 10.1242/jcs.003111. View

Mukhopadhyay S, Bachert C, Smith D, Linstedt A . Manganese-induced trafficking and turnover of the cis-Golgi glycoprotein GPP130. Mol Biol Cell. 2010; 21(7):1282-92. PMC: 2847531. DOI: 10.1091/mbc.e09-11-0985. View

Linstedt A, Mehta A, Suhan J, Reggio H, Hauri H . Sequence and overexpression of GPP130/GIMPc: evidence for saturable pH-sensitive targeting of a type II early Golgi membrane protein. Mol Biol Cell. 1997; 8(6):1073-87. PMC: 305715. DOI: 10.1091/mbc.8.6.1073. View

Moreno J, Yeomans E, Streifel K, Brattin B, Taylor R, Tjalkens R . Age-dependent susceptibility to manganese-induced neurological dysfunction. Toxicol Sci. 2009; 112(2):394-404. PMC: 2777078. DOI: 10.1093/toxsci/kfp220. View

Mallard F, Johannes L . Shiga toxin B-subunit as a tool to study retrograde transport. Methods Mol Med. 2002; 73:209-20. DOI: 10.1385/1-59259-316-x:209. View

Johannes L, Tenza D, Antony C, Goud B . Retrograde transport of KDEL-bearing B-fragment of Shiga toxin. J Biol Chem. 1997; 272(31):19554-61. DOI: 10.1074/jbc.272.31.19554. View

Ishikawa S, Kawahara K, Kagami Y, Isshiki Y, Kaneko A, Matsui H . Protection against Shiga toxin 1 challenge by immunization of mice with purified mutant Shiga toxin 1. Infect Immun. 2003; 71(6):3235-9. PMC: 155758. DOI: 10.1128/IAI.71.6.3235-3239.2003. View

Mukhopadhyay S, Linstedt A . Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity. Proc Natl Acad Sci U S A. 2010; 108(2):858-63. PMC: 3021037. DOI: 10.1073/pnas.1013642108. View

10.

Stechmann B, Bai S, Gobbo E, Lopez R, Merer G, Pinchard S . Inhibition of retrograde transport protects mice from lethal ricin challenge. Cell. 2010; 141(2):231-42. DOI: 10.1016/j.cell.2010.01.043. View

11.

Mohawk K, Melton-Celsa A, Zangari T, Carroll E, OBrien A . Pathogenesis of Escherichia coli O157:H7 strain 86-24 following oral infection of BALB/c mice with an intact commensal flora. Microb Pathog. 2010; 48(3-4):131-42. PMC: 2834854. DOI: 10.1016/j.micpath.2010.01.003. View

12.

Sandvig K, van Deurs B . Delivery into cells: lessons learned from plant and bacterial toxins. Gene Ther. 2005; 12(11):865-72. DOI: 10.1038/sj.gt.3302525. View

13.

Shin I, Ishii S, Shin J, Sung K, Park B, Jang H . Globotriaosylceramide (Gb3) content in HeLa cells is correlated to Shiga toxin-induced cytotoxicity and Gb3 synthase expression. BMB Rep. 2009; 42(5):310-4. DOI: 10.5483/bmbrep.2009.42.5.310. View

14.

Wong C, Jelacic S, Habeeb R, Watkins S, Tarr P . The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000; 342(26):1930-6. PMC: 3659814. DOI: 10.1056/NEJM200006293422601. View

15.

Tesh V, Burris J, Owens J, Gordon V, Wadolkowski E, OBrien A . Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice. Infect Immun. 1993; 61(8):3392-402. PMC: 281015. DOI: 10.1128/iai.61.8.3392-3402.1993. View

16.

Natarajan R, Linstedt A . A cycling cis-Golgi protein mediates endosome-to-Golgi traffic. Mol Biol Cell. 2004; 15(11):4798-806. PMC: 524728. DOI: 10.1091/mbc.e04-05-0366. View

17.

Mohawk K, OBrien A . Mouse models of Escherichia coli O157:H7 infection and shiga toxin injection. J Biomed Biotechnol. 2011; 2011:258185. PMC: 3022220. DOI: 10.1155/2011/258185. View

18.

Mallard F, Antony C, Tenza D, Salamero J, Goud B, Johannes L . Direct pathway from early/recycling endosomes to the Golgi apparatus revealed through the study of shiga toxin B-fragment transport. J Cell Biol. 1998; 143(4):973-90. PMC: 2132951. DOI: 10.1083/jcb.143.4.973. View

19.

Aschner M, Erikson K, Herrero Hernandez E, Tjalkens R . Manganese and its role in Parkinson's disease: from transport to neuropathology. Neuromolecular Med. 2009; 11(4):252-66. PMC: 4613768. DOI: 10.1007/s12017-009-8083-0. View

20.

Puri S, Bachert C, Fimmel C, Linstedt A . Cycling of early Golgi proteins via the cell surface and endosomes upon lumenal pH disruption. Traffic. 2002; 3(9):641-53. DOI: 10.1034/j.1600-0854.2002.30906.x. View