tailieunhanh - Báo cáo khoa hoc : Matrix metalloproteinase proteolysis of the mycobacterial HSP65 protein as a potential source of immunogenic peptides in human tuberculosis

Mycobacterium tuberculosisis the causative agent of human tuberculosis (TB). Mycobacterial secretory protein ESAT-6 induces matrix metallopro-teinase (MMP)-9 in epithelial cells neighboring infected macrophages. MMP-9 then enhances recruitment of uninfected macrophages, which con-tribute to nascent granuloma maturation and bacterial growth. | IFEBS Journal Matrix metalloproteinase proteolysis of the mycobacterial HSP65 protein as a potential source of immunogenic peptides in human tuberculosis Sergey A. Shiryaev1 Piotr Cieplak1 Alexander E. Aleshin1 Qing Sun1 Wenhong Zhu1 Khatereh Motamedchaboki1 Alexander Sloutsky2 and Alex Y. Strongin1 1 Infectious and Inflammatory Disease Center Sanford-Burnham MedicalResearch Institute La Jolla CA USA 2 Department of Medicine University of Massachusetts Medical School Shrewsbury MA USA Keywords HSP65 MMP Mycobacterium proteolysis tuberculosis Correspondence A. Y. Strongin Sanford-Burnham Medical Research Institute 10907 North Torrey Pines Road La Jolla CA 92037 USA Fax 1 858 795 5225 Tel 1 858 795 5271 E-mail strongin@ A. Sloutsky Department of Medicine University of Massachusetts Medical School 333 South Street Shrewsbury MA 01545 USA Fax 1 617 983 6399 Tel 1 617 983 6370 E-mail Received 5 June 2011 revised 5 July 2011 accepted 11 July 2011 doi 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.