Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus

ABSTRACT Group A streptococcus (GAS) is an important human pathogen that causes a wide variety of cutaneous and systemic infections. Although originally thought to be an extracellular bacterium, numerous studies have demonstrated that GAS can trigger internalization into nonimmune cells to escape fr...

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Autores principales:	Yi-Lin Cheng, Yan-Wei Wu, Chih-Feng Kuo, Shiou-Ling Lu, Fu-Tong Liu, Robert Anderson, Chiou-Feng Lin, Yi-Ling Liu, Wan-Yu Wang, Ying-Da Chen, Po-Xing Zheng, Jiunn-Jong Wu, Yee-Shin Lin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	galectin-3 galectin-8 group A streptococcus parkin ubiquitin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/71493919986846eaa50379e579f50135
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spelling	oai:doaj.org-article:71493919986846eaa50379e579f501352021-11-15T15:51:43ZGalectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus10.1128/mBio.00899-172150-7511https://doaj.org/article/71493919986846eaa50379e579f501352017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00899-17https://doaj.org/toc/2150-7511ABSTRACT Group A streptococcus (GAS) is an important human pathogen that causes a wide variety of cutaneous and systemic infections. Although originally thought to be an extracellular bacterium, numerous studies have demonstrated that GAS can trigger internalization into nonimmune cells to escape from immune surveillance or antibiotic-mediated killing. Epithelial cells possess a defense mechanism involving autophagy-mediated targeting and killing of GAS within lysosome-fused autophagosomes. In endothelial cells, in contrast, we previously showed that autophagy is not sufficient for GAS killing. In the present study, we showed higher galectin-3 (Gal-3) expression and lower Gal-8 expression in endothelial cells than in epithelial cells. The recruitment of Gal-3 to GAS is higher and the recruitment of Gal-8 to GAS is lower in endothelial cells than in epithelial cells. We further showed that Gal-3 promotes GAS replication and diminishes the recruitment of Gal-8 and ubiquitin, the latter of which is a critical protein for autophagy sequestration. After knockdown of Gal-3 in endothelial cells, the colocalization of Gal-8, parkin, and ubiquitin-decorated GAS is significantly increased, as is the interaction of Gal-8 and parkin, an E3 ligase. Furthermore, inhibition of Gal-8 in epithelial cells attenuates recruitment of parkin; both Gal-8 and parkin contribute to ubiquitin recruitment and GAS elimination. Animal studies confirmed that Gal-3-knockout mice develop less-severe skin damage and that GAS replication can be detected only in the air pouch and not in organs and endothelial cells. These results demonstrate that Gal-3 inhibits ubiquitin recruitment by blocking Gal-8 and parkin recruitment, resulting in GAS replication in endothelial cells. IMPORTANCE In epithelial cells, GAS can be efficiently killed within the lysosome-fused autophaosome compartment. However, we previously showed that, in spite of LC-3 recruitment, the autophagic machinery is not sufficient for GAS killing in endothelial cells. In this report, we provide the first evidence that Gal-3, highly expressed in endothelial cells, blocks the tagging of ubiquitin to GAS by inhibiting recruitment of Gal-8 and parkin, leading to an enhancement of GAS replication. We also provide the first demonstration that Gal-8 can interact with parkin, the critical E3 ligase, for resistance to intracellular bacteria by facilitating the decoration of bacteria with ubiquitin chains. Our findings reveal that differential levels of Gal-3 and Gal-8 expression and recruitment to GAS between epithelial cells and endothelial cells may contribute to the different outcomes of GAS elimination or survival and growth of GAS in these two types of cells.Yi-Lin ChengYan-Wei WuChih-Feng KuoShiou-Ling LuFu-Tong LiuRobert AndersonChiou-Feng LinYi-Ling LiuWan-Yu WangYing-Da ChenPo-Xing ZhengJiunn-Jong WuYee-Shin LinAmerican Society for Microbiologyarticlegalectin-3galectin-8group A streptococcusparkinubiquitinMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	galectin-3 galectin-8 group A streptococcus parkin ubiquitin Microbiology QR1-502
spellingShingle	galectin-3 galectin-8 group A streptococcus parkin ubiquitin Microbiology QR1-502 Yi-Lin Cheng Yan-Wei Wu Chih-Feng Kuo Shiou-Ling Lu Fu-Tong Liu Robert Anderson Chiou-Feng Lin Yi-Ling Liu Wan-Yu Wang Ying-Da Chen Po-Xing Zheng Jiunn-Jong Wu Yee-Shin Lin Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
description	ABSTRACT Group A streptococcus (GAS) is an important human pathogen that causes a wide variety of cutaneous and systemic infections. Although originally thought to be an extracellular bacterium, numerous studies have demonstrated that GAS can trigger internalization into nonimmune cells to escape from immune surveillance or antibiotic-mediated killing. Epithelial cells possess a defense mechanism involving autophagy-mediated targeting and killing of GAS within lysosome-fused autophagosomes. In endothelial cells, in contrast, we previously showed that autophagy is not sufficient for GAS killing. In the present study, we showed higher galectin-3 (Gal-3) expression and lower Gal-8 expression in endothelial cells than in epithelial cells. The recruitment of Gal-3 to GAS is higher and the recruitment of Gal-8 to GAS is lower in endothelial cells than in epithelial cells. We further showed that Gal-3 promotes GAS replication and diminishes the recruitment of Gal-8 and ubiquitin, the latter of which is a critical protein for autophagy sequestration. After knockdown of Gal-3 in endothelial cells, the colocalization of Gal-8, parkin, and ubiquitin-decorated GAS is significantly increased, as is the interaction of Gal-8 and parkin, an E3 ligase. Furthermore, inhibition of Gal-8 in epithelial cells attenuates recruitment of parkin; both Gal-8 and parkin contribute to ubiquitin recruitment and GAS elimination. Animal studies confirmed that Gal-3-knockout mice develop less-severe skin damage and that GAS replication can be detected only in the air pouch and not in organs and endothelial cells. These results demonstrate that Gal-3 inhibits ubiquitin recruitment by blocking Gal-8 and parkin recruitment, resulting in GAS replication in endothelial cells. IMPORTANCE In epithelial cells, GAS can be efficiently killed within the lysosome-fused autophaosome compartment. However, we previously showed that, in spite of LC-3 recruitment, the autophagic machinery is not sufficient for GAS killing in endothelial cells. In this report, we provide the first evidence that Gal-3, highly expressed in endothelial cells, blocks the tagging of ubiquitin to GAS by inhibiting recruitment of Gal-8 and parkin, leading to an enhancement of GAS replication. We also provide the first demonstration that Gal-8 can interact with parkin, the critical E3 ligase, for resistance to intracellular bacteria by facilitating the decoration of bacteria with ubiquitin chains. Our findings reveal that differential levels of Gal-3 and Gal-8 expression and recruitment to GAS between epithelial cells and endothelial cells may contribute to the different outcomes of GAS elimination or survival and growth of GAS in these two types of cells.
format	article
author	Yi-Lin Cheng Yan-Wei Wu Chih-Feng Kuo Shiou-Ling Lu Fu-Tong Liu Robert Anderson Chiou-Feng Lin Yi-Ling Liu Wan-Yu Wang Ying-Da Chen Po-Xing Zheng Jiunn-Jong Wu Yee-Shin Lin
author_facet	Yi-Lin Cheng Yan-Wei Wu Chih-Feng Kuo Shiou-Ling Lu Fu-Tong Liu Robert Anderson Chiou-Feng Lin Yi-Ling Liu Wan-Yu Wang Ying-Da Chen Po-Xing Zheng Jiunn-Jong Wu Yee-Shin Lin
author_sort	Yi-Lin Cheng
title	Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
title_short	Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
title_full	Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
title_fullStr	Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
title_full_unstemmed	Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus
title_sort	galectin-3 inhibits galectin-8/parkin-mediated ubiquitination of group a streptococcus
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/71493919986846eaa50379e579f50135
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Galectin-3 Inhibits Galectin-8/Parkin-Mediated Ubiquitination of Group A Streptococcus

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