Streptolysin S induces mitochondrial damage and macrophage death through inhibiting degradation of glycogen synthase kinase-3β in Streptococcus pyogenes infection

Nina Tsao, Chih Feng Kuo, Miao Hui Cheng, Wei Chen Lin, Chiou Feng Lin, Yee Shin Lin

Research output: Contribution to journalArticle

Abstract

Group A Streptococcus (GAS) infection is associated with a variety of human diseases. Previous studies indicate GAS infection leads to RAW264.7 cell death, but the mechanism is unclear. Here, analyzing the timing of reactive oxygen species (ROS) production and using mitochondrial ROS scavenger, we found the wild type GAS-induced RAW264.7 cell death was associated with mitochondrial ROS. The wild type GAS infection could activate glycogen synthase kinase-3β (GSK-3β). Inhibition of GSK-3β activity by lithium chloride or decreasing GSK-3β expression by lentivirus-mediated short hairpin RNA for GSK-3β could not only decrease the wild type GAS-induced mitochondrial ROS generation, mitochondria damage and cell death, but also reduced GAS intracellular replication. Streptolysin S (SLS), a GAS toxin, played the important role on GAS-induced macrophage death. Compared to the wild type GAS with its isogenic sagB mutant (SLS mutant)-infected macrophages, we found sagB mutant infection caused less mitochondrial ROS generation and cell death than those of the wild type GAS-infected ones. Furthermore, the sagB mutant, but not the wild type or the sagB-complementary mutant, could induce GSK-3β degradation via a proteasome-dependent pathway. These results suggest that a new mechanism of SLS-induced macrophage death was through inhibiting GSK-3β degradation and further enhancing mitochondrial damage.

Original languageEnglish
Article number5371
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Glycogen Synthase Kinase 3
Streptococcus pyogenes
Streptococcus
Macrophages
Infection
Reactive Oxygen Species
Cell Death
streptolysin S
Lithium Chloride
Lentivirus
Proteasome Endopeptidase Complex
Small Interfering RNA
Mitochondria

ASJC Scopus subject areas

  • General

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Streptolysin S induces mitochondrial damage and macrophage death through inhibiting degradation of glycogen synthase kinase-3β in Streptococcus pyogenes infection. / Tsao, Nina; Kuo, Chih Feng; Cheng, Miao Hui; Lin, Wei Chen; Lin, Chiou Feng; Lin, Yee Shin.

In: Scientific Reports, Vol. 9, No. 1, 5371, 01.12.2019.

Research output: Contribution to journalArticle

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