Cyclic diGMP regulates production of sortase substrates of Clostridium difficile and their surface exposure through zmpI protease-mediate cleavage

Peltier, J., et al. The Journal of biological chemistry 290, 24453-24469 (2015).

Speaker: Jyun-Cyuan Chang (張鈞筌)             Time: 15:00~16:00, Mar. 2, 2016

Commentator: Dr. I-Hsiu Huang (黃一修 老師)     Place: Room 601

Abstract

Clostridium difficile is a Gram-positive, spore-forming anaerobic bacteria. Clostridium difficile infection is associated with broad-spectrum antibiotic therapy and the major cause of infectious diarrhea for hospitalized patients¹. Bacterial adhesive surface structures, especially bacterial pilus and surface proteins, can function as adhesins which are critical to the pathogenesis of C. difficile in the colonization process². In Gram-positive bacteria, surface proteins act as virulence factors and are covalently anchored to the bacterial peptidoglycan of cell wall by sortase, a cysteinetranspeptidase enzyme. C. difficile has only one conserved sortase gene which is similar to class B sortase and is annotated as sortase B (SrtB). However, the mechanism of SrtB anchoring proteins to the cell wall of C. difficile is still unclear. In this study, the authors identified two C. difficilesortase substrates, CD2831 and CD3246, which are collagen-binding proteins covalent attached to the peptidoglycan by catalytic activity of sortase. In addition, the authors also determined the cell wall anchor structures of CD2831. CD2831 is also a target of metalloprotease ZmpI (CD2830) that is cleaved at the C-terminal and released into the culture supernatant. Cyclic diGMP(c-diGMP) is a secondary messenger used in signal transduction in bacteria. In this paper, the authors showed that CD2831 is elevated and anchored to the peptidoglycan of cell wall when intracellular cyclicdiGMP (c-diGMP) concentration is high. In the contrast, when c-diGMP levels are low, CD2831 is efficiently cleaved and released into the supernatant by ZmpI. CD2831 and ZmpI are inversely controlled by c-diGMP. The authors further showed that expression of CD2831 and CD3246, which are proteolytically cleaved by ZmpI, are controlled by c-diGMP concentration. Taken together, the data revealed a novel association of sortase activity with c-diGMP-mediated regulation to control levels of cell wall anchoring and secretion of putative adhesion molecules.

References:

1.         Leffler, D.A. & Lamont, J.T. Clostridium difficile infection. The New England journal of medicine 372, 1539-1548 (2015).

2.         Kline, K.A., Falker, S., Dahlberg, S., Normark, S. & Henriques-Normark, B. Bacterial adhesins in host-microbe interactions. Cell host & microbe 5, 580-592 (2009).