Author contribution: S.M.U., P.D. and O.H.W. designed research; S.M.U., J.E., M.F. and O.H.W. performed research; M.H. and M.M. provided quality controlled SLO mutant, S.M.U., J.E., P.M., M.F. and O.H.W. analysed data; S.M.U., P.D. and O.H.W. wrote the paper.
Molecular basis of early epithelial response to streptococcal exotoxin: role of STIM1 and Orai1 proteins
Article first published online: 13 DEC 2011
© 2011 Blackwell Publishing Ltd
Volume 14, Issue 3, pages 299–315, March 2012
How to Cite
Usmani, S. M., von Einem, J., Frick, M., Miklavc, P., Mayenburg, M., Husmann, M., Dietl, P. and Wittekindt, O. H. (2012), Molecular basis of early epithelial response to streptococcal exotoxin: role of STIM1 and Orai1 proteins. Cellular Microbiology, 14: 299–315. doi: 10.1111/j.1462-5822.2011.01724.x
- Issue published online: 22 FEB 2012
- Article first published online: 13 DEC 2011
- Accepted manuscript online: 10 NOV 2011 08:03AM EST
- Received 7 March, 2011; revised 24 October, 2011; accepted 28 October, 2011.
Streptolysin O (SLO) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pyogenes. SLO induces diverse types of Ca2+ signalling in host cells which play a key role in membrane repair and cell fate determination. The mechanisms behind SLO-induced Ca2+ signalling remain poorly understood. Here, we show that in NCI-H441 cells, wild-type SLO as well as non-pore-forming mutant induces long-lasting intracellular Ca2+ oscillations via IP3-mediated depletion of intracellular stores and activation of store-operated Ca2+ (SOC) entry. SLO-induced activation of SOC entry was confirmed by Ca2+ add-back experiments, pharmacologically and by overexpression as well as silencing of STIM1 and Orai1 expression. SLO also activated SOC entry in primary cultivated alveolar type II (ATII) cells but Ca2+ oscillations were comparatively short-lived in nature. Comparison of STIM1 and Orai1 revealed a differential expression pattern in H441 and ATII cells. Overexpression of STIM1 and Orai1 proteins in ATII cells changed the short-lived oscillatory response into a long-lived one. Thus, we conclude that SLO-mediated Ca2+ signalling involves Ca2+ release from intracellular stores and STIM1/Orai1-dependent SOC entry. The phenotype of Ca2+ signalling depends on STIM1 and Orai1 expression levels. Our findings suggest a new role for SOC entry-associated proteins in S. pyogenes-induced lung infection and pneumonia.