Molecular basis of early epithelial response to streptococcal exotoxin: role of STIM1 and Orai1 proteins: Streptolysin O activates SOC entry

Usmani, Shariq M.; von Einem, Jens; Frick, Manfred; Miklavc, Pika; Mayenburg, Martina; Husmann, Matthias; Dietl, Paul; Wittekindt, Oliver H.

Abstract

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.

• Journal Article Type: Article
• Online Publication Date: Dec 13, 2011
• Publication Date: 2012-03
• Deposit Date: Mar 4, 2024
• Journal: Cellular Microbiology
• Print ISSN: 1462-5814
• Electronic ISSN: 1462-5822
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 3
• Pages: 299-315
• DOI: https://doi.org/10.1111/j.1462-5822.2011.01724.x
• Keywords: Virology; Immunology; Microbiology