Document Detail

The diphthamide modification on elongation factor-2 renders mammalian cells resistant to ricin.
MedLine Citation:
PMID:  18460012     Owner:  NLM     Status:  MEDLINE    
Diphthamide is a post-translational derivative of histidine in protein synthesis elongation factor-2 (eEF-2) that is present in all eukaryotes with no known normal physiological role. Five proteins Dph1-Dph5 are required for the biosynthesis of diphthamide. Chinese hamster ovary (CHO) cells mutated in the biosynthetic genes lack diphthamide and are resistant to bacterial toxins such as diphtheria toxin. We found that diphthamide-deficient cultured cells were threefold more sensitive than their parental cells towards ricin, a ribosome-inactivating protein (RIP). RIPs bind to ribosomes at the same site as eEF-2 and cleave the large ribosomal RNA, inhibiting translation and causing cell death. We hypothesized that one role of diphthamide may be to protect ribosomes, and therefore all eukaryotic life forms, from RIPs, which are widely distributed in nature. A protective role of diphthamide against ricin was further demonstrated by complementation where dph mutant CHO cells transfected with the corresponding DPH gene acquired increased resistance to ricin in comparison with the control-transfected cells, and resembled the parental CHO cells in their response to the toxin. These data show that the presence of diphthamide in eEF-2 provides protection against ricin and suggest the hypothesis that diphthamide may have evolved to provide protection against RIPs.
Pradeep K Gupta; Shihui Liu; Mariska P Batavia; Stephen H Leppla
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2008-05-05
Journal Detail:
Title:  Cellular microbiology     Volume:  10     ISSN:  1462-5822     ISO Abbreviation:  Cell. Microbiol.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-20     Completed Date:  2008-09-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  100883691     Medline TA:  Cell Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1687-94     Citation Subset:  IM    
Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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MeSH Terms
CHO Cells
Chemical Warfare Agents / pharmacology*
Drug Resistance*
Histidine / analogs & derivatives*,  metabolism
Peptide Elongation Factor 2 / metabolism*
Protein Processing, Post-Translational*
Proteins / genetics,  metabolism
Ricin / pharmacology*
Grant Support
Z01 AI000929-05/AI/NIAID NIH HHS
Reg. No./Substance:
0/Chemical Warfare Agents; 0/Peptide Elongation Factor 2; 0/Proteins; 71-00-1/Histidine; 75645-22-6/diphthamide; 9009-86-3/Ricin

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