Document Detail


A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen.
MedLine Citation:
PMID:  9234799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several bacterial protein toxins require activation by eukaryotic proteases. Previous studies have shown that anthrax toxin protective antigen (PA), Pseudomonas exotoxin A (PE), and diphtheria toxin (DT) are cleaved by furin C-terminal to the sequences RKKR, RQPR, and RVRR, respectively. Because furin-deficient cells retain some sensitivity to PA and DT, it is evident that other cellular proteases can activate these toxins. Whereas furin has been shown to require arginine residues at positions -1 and -4 for substrate recognition, another protease with an activity which could substitute for furin in toxin activation, the furin-related protease PACE4, requires basic residues in the -1, -2, and -4 positions of the substrate sequence. To examine the relative roles of furin and PACE4 in toxin activation, we used furin-deficient CHO cells (FD11 cells) transfected with either the furin (FD11/furin cells) or PACE4 (FD11/PACE4 cells) gene. Mutant PA proteins containing the cleavage sequence RAAR or KR were cytotoxic toward cells expressing only PACE4. In vitro cleavage data demonstrated that PACE4 can recognize RAAR and, to a much lesser extent, KR and RR. When extracts from PACE4-transfected cells were used as a source of proteases, PACE4 had minimal activity, indicating that it had been partially inactivated or did not remain associated with the cell membranes. Cleavage of iodinated PA containing the sequence RKKR or RAAR was detected on the surface of all cell types tested, but cleavage of a dibasic sequence was detected only intracellularly and only in cells that expressed furin or PACE4. The data provide evidence that PACE4 is present at the exterior of cells, that it plays a role in the proteolytic activation of anthrax toxin PA, and that PACE4 can activate substrates at the sequence RAAR or KR.
Authors:
V M Gordon; A Rehemtulla; S H Leppla
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Infection and immunity     Volume:  65     ISSN:  0019-9567     ISO Abbreviation:  Infect. Immun.     Publication Date:  1997 Aug 
Date Detail:
Created Date:  1997-08-14     Completed Date:  1997-08-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3370-5     Citation Subset:  IM    
Affiliation:
Laboratory of Microbial Ecology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA. gordon@yoda.nidr.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, Bacterial*
Bacterial Toxins / metabolism*
CHO Cells
Cricetinae
Furin
Serine Endopeptidases / physiology*
Subtilisins / physiology
Transfection
Chemical
Reg. No./Substance:
0/Antigens, Bacterial; 0/Bacterial Toxins; 0/anthrax toxin; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.-/Subtilisins; EC 3.4.21.75/Furin
Comments/Corrections

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