Document Detail

Matrix metalloproteinase proteolysis of the mycobacterial HSP65 protein as a potential source of immunogenic peptides in human tuberculosis.
MedLine Citation:
PMID:  21752195     Owner:  NLM     Status:  MEDLINE    
Mycobacterium tuberculosis is the causative agent of human tuberculosis (TB). Mycobacterial secretory protein ESAT-6 induces matrix metalloproteinase (MMP)-9 in epithelial cells neighboring infected macrophages. MMP-9 then enhances recruitment of uninfected macrophages, which contribute to nascent granuloma maturation and bacterial growth. Disruption of MMP-9 function attenuates granuloma formation and bacterial growth. The abundant mycobacterial 65 kDa heat shock protein (HSP65) chaperone is the major target for the immune response and a critical component in M. tuberculosis adhesion to macrophages. We hypothesized that HSP65 is susceptible to MMP-9 proteolysis and that the resulting HSP65 immunogenic peptides affect host adaptive immunity. To identify MMPs that cleave HSP65, we used MMP-2 and MMP-9 gelatinases, the simple hemopexin domain MMP-8, membrane-associated MMP-14, MMP-15, MMP-16 and MMP-24, and glycosylphosphatidylinositol-linked MMP-17 and MMP-25. We determined both the relative cleavage efficiency of MMPs against the HSP65 substrate and the peptide sequence of the cleavage sites. Cleavage of the unstructured PAGHG474L C-terminal region initiates the degradation of HSP65 by MMPs. This initial cleavage destroys the substrate-binding capacity of the HSP65 chaperone. Multiple additional cleavages of the unfolded HSP65 then follow. MMP-2, MMP-8, MMP-14, MMP-15 and MMP-16, in addition to MMP-9, generate the known highly immunogenic N-terminal peptide of HSP65. Based on our biochemical data, we now suspect that MMP proteolysis of HSP65 in vivo, including MMP-9 proteolysis, also results in the abundant generation of the N-terminal immunogenic peptide and that this peptide, in addition to intact HSP65, contributes to the complex immunomodulatory interplay in the course of TB infection.
Sergey A Shiryaev; Piotr Cieplak; Alexander E Aleshin; Qing Sun; Wenhong Zhu; Khatereh Motamedchaboki; Alexander Sloutsky; Alex Y Strongin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-08
Journal Detail:
Title:  The FEBS journal     Volume:  278     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-07     Completed Date:  2011-11-09     Revised Date:  2014-04-18    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  England    
Other Details:
Languages:  eng     Pagination:  3277-86     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors Journal compilation © 2011 FEBS.
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MeSH Terms
Adaptive Immunity
Amino Acid Sequence
Antigens, Bacterial / chemistry,  metabolism*
Bacterial Proteins / chemistry,  metabolism*
Catalytic Domain
Chaperonin 60 / chemistry,  metabolism*
Epitopes / chemistry,  metabolism
Hydrolysis / drug effects
Isoenzymes / antagonists & inhibitors,  metabolism
Matrix Metalloproteinase 9 / genetics,  metabolism
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases / genetics,  metabolism*
Molecular Sequence Data
Mycobacterium tuberculosis / immunology*
Peptide Fragments / antagonists & inhibitors,  chemistry,  genetics,  metabolism*
Protease Inhibitors / pharmacology
Recombinant Proteins / antagonists & inhibitors,  chemistry,  metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Substrate Specificity
Tuberculosis / immunology*,  prevention & control
Grant Support
CA77470/CA/NCI NIH HHS; CA83017/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS; R01 CA083017/CA/NCI NIH HHS; R01 CA083017-14/CA/NCI NIH HHS; R01 CA157328/CA/NCI NIH HHS; R01 CA157328-02/CA/NCI NIH HHS; U01 AI061139/AI/NIAID NIH HHS; U01 AI061139-05/AI/NIAID NIH HHS
Reg. No./Substance:
0/Antigens, Bacterial; 0/Bacterial Proteins; 0/Chaperonin 60; 0/Epitopes; 0/Isoenzymes; 0/Matrix Metalloproteinase Inhibitors; 0/Peptide Fragments; 0/Protease Inhibitors; 0/Recombinant Proteins; 0/heat-shock protein 65, Mycobacterium; EC 3.4.24.-/Matrix Metalloproteinases; EC Metalloproteinase 9

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