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Targeting botulinum neurotoxin persistence by the ubiquitin-proteasome system

  1. Author:
    Tsai, Y. C.
    Maditz, R.
    Kuo, C. L.
    Fishman, P. S.
    Shoemaker, C. B.
    Oyler, G. A.
    Weissman, A. M.

  2. Author Address

    [Oyler, George A.] Synapt Res LLC, Baltimore, MD 21227 USA. [Tsai, Yien Che; Maditz, Rhyan; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Kuo, Chueh-ling; Shoemaker, Charles B.] Tufts Cummings Sch Vet Med, Dept Biomed Sci Infect Dis, North Grafton, MA 01536 USA. [Fishman, Paul S.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Fishman, Paul S.] Maryland Dept Vet Affairs Hlth Care Syst, Neurol Serv, Baltimore, MD 21201 USA.;Oyler, GA, Synapt Res LLC, Baltimore, MD 21227 USA.;george@synapticresearch.com amw@nih.gov
    1. Year: 2010
    2. Date: Sep
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 107
    2. 38
    3. Pages: 16554-16559
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    Botulinum neurotoxins (BoNTs) are the most potent natural toxins known. The effects of BoNT serotype A (BoNT/A) can last several months, whereas the effects of BoNT serotype E (BoNT/E), which shares the same synaptic target, synaptosomal-associated protein 25 (SNAP25), last only several weeks. The long-lasting effects or persistence of BoNT/A, although desirable for therapeutic applications, presents a challenge for medical treatment of BoNT intoxication. Although the mechanisms for BoNT toxicity are well known, little is known about the mechanisms that govern the persistence of the toxins. We show that the recombinant catalytic light chain (LC) of BoNT/E is ubiquitylated and rapidly degraded in cells. In contrast, BoNT/A LC is considerably more stable. Differential susceptibility of the catalytic LCs to ubiquitin-dependent proteolysis therefore might explain the differential persistence of BoNT serotypes. In this regard we show that TRAF2, a RING finger protein implicated in ubiquitylation, selectively associates with BoNT/E LC and promotes its proteasomal degradation. Given these data, we asked whether BoNT/A LC could be targeted for rapid proteasomal degradation by redirecting it to characterized ubiquitin ligase domains. We describe chimeric SNAP25-based ubiquitin ligases that target BoNT/A LC for degradation, reducing its duration in a cellular model for toxin persistence.

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External Sources

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  2. DOI: 10.1073/pnas.1008302107
  3. View record in Web of Science®
  4. WOS: 000282003700033

Library Notes

  1. Fiscal Year: FY2009-2010
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