Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection

ABSTRACT Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is...

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Autores principales: Jiachao Wang, Meiqi Meng, Miao Li, Xiaofei Guan, Jianguo Liu, Xue Gao, Qingqing Sun, Jinquan Li, Cuiqing Ma, Lin Wei
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:5f19651063dd419e9bfe8742dc2d0e0b2021-11-15T15:56:46ZIntegrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection10.1128/mBio.00771-202150-7511https://doaj.org/article/5f19651063dd419e9bfe8742dc2d0e0b2020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00771-20https://doaj.org/toc/2150-7511ABSTRACT Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is an important strategy for nonphagocytes to eliminate intracellular bacteria. Upon pathogen recognition, cell surface receptors can directly trigger autophagy, which is a critical step in controlling infection. However, the mechanisms of how cells sense invading bacteria and use this information specifically to trigger autophagy remain unclear. In this study, we stimulated cells and infected mice with M and FbaA mutants of M1 GAS strain SF370 or with purified M and FbaA proteins (two critical surface structural proteins of GAS), and found that only FbaA protein was involved in autophagy induction. Furthermore, the FbaA protein induced autophagy independent of common pattern recognition receptors (such as Toll-like receptors); rather, it relies on binding to integrin α5β1 expressed on the cell surface, which is mediated by extracellular matrix protein fibronectin (Fn). The FbaA-Fn-integrin α5β1 complex activates Beclin-1 through the mTOR-ULK1–Beclin-1 pathway, which enables the Beclin-1/Vps34 complex to recruit Rab7 and, ultimately, to promote the formation of autophagosomes. By knocking down integrin α5β1, Fn, Atg5, Beclin-1, and ULK1 in Hep2 cells and deleting Atg5 or integrin α5β1 in mice, we reveal a novel role for integrin α5β1 in inducing autophagy. Our study demonstrates that integrin α5β1, through interacting with pathogen components, initiates effective host innate immunity against invading intracellular pathogens. IMPORTANCE Autophagy is generally considered a strategy used by the innate immune system to eliminate invasive pathogens through capturing and transferring them to lysosomes. Currently, researchers pay more attention to how virulence factors secreted by GAS regulate the autophagic process. Here, we provide the first evidence that the structural protein FbaA of M1 GAS strain SF370 is a potent inducer of autophagy in epithelial cells. Furthermore, we demonstrate that integrin α5β1 in epithelial cells in vitro and in vivo acts as a receptor to initiate the signaling for inducing autophagy by binding to FbaA of M1 GAS strain SF370 via Fn. Our study reveals the underlying mechanisms by which pathogens induce Fn-integrin α5β1 to trigger autophagy in a conserved pattern in epithelial cells.Jiachao WangMeiqi MengMiao LiXiaofei GuanJianguo LiuXue GaoQingqing SunJinquan LiCuiqing MaLin WeiAmerican Society for Microbiologyarticleautophagygroup A StreptococcusFbaA proteinintegrin α5β1fibronectinMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution DOAJ
collection DOAJ
language EN
topic autophagy
group A Streptococcus
FbaA protein
integrin α5β1
fibronectin
Microbiology
QR1-502
spellingShingle autophagy
group A Streptococcus
FbaA protein
integrin α5β1
fibronectin
Microbiology
QR1-502
Jiachao Wang
Meiqi Meng
Miao Li
Xiaofei Guan
Jianguo Liu
Xue Gao
Qingqing Sun
Jinquan Li
Cuiqing Ma
Lin Wei
Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
description ABSTRACT Group A Streptococcus (GAS), one of the most common extracellular pathogens, has been reported to invade epithelial and endothelial cells. Our results reveal that M1 GAS strain SF370 can be effectively eliminated by respiratory epithelial cells. Emerging evidence indicates that autophagy is an important strategy for nonphagocytes to eliminate intracellular bacteria. Upon pathogen recognition, cell surface receptors can directly trigger autophagy, which is a critical step in controlling infection. However, the mechanisms of how cells sense invading bacteria and use this information specifically to trigger autophagy remain unclear. In this study, we stimulated cells and infected mice with M and FbaA mutants of M1 GAS strain SF370 or with purified M and FbaA proteins (two critical surface structural proteins of GAS), and found that only FbaA protein was involved in autophagy induction. Furthermore, the FbaA protein induced autophagy independent of common pattern recognition receptors (such as Toll-like receptors); rather, it relies on binding to integrin α5β1 expressed on the cell surface, which is mediated by extracellular matrix protein fibronectin (Fn). The FbaA-Fn-integrin α5β1 complex activates Beclin-1 through the mTOR-ULK1–Beclin-1 pathway, which enables the Beclin-1/Vps34 complex to recruit Rab7 and, ultimately, to promote the formation of autophagosomes. By knocking down integrin α5β1, Fn, Atg5, Beclin-1, and ULK1 in Hep2 cells and deleting Atg5 or integrin α5β1 in mice, we reveal a novel role for integrin α5β1 in inducing autophagy. Our study demonstrates that integrin α5β1, through interacting with pathogen components, initiates effective host innate immunity against invading intracellular pathogens. IMPORTANCE Autophagy is generally considered a strategy used by the innate immune system to eliminate invasive pathogens through capturing and transferring them to lysosomes. Currently, researchers pay more attention to how virulence factors secreted by GAS regulate the autophagic process. Here, we provide the first evidence that the structural protein FbaA of M1 GAS strain SF370 is a potent inducer of autophagy in epithelial cells. Furthermore, we demonstrate that integrin α5β1 in epithelial cells in vitro and in vivo acts as a receptor to initiate the signaling for inducing autophagy by binding to FbaA of M1 GAS strain SF370 via Fn. Our study reveals the underlying mechanisms by which pathogens induce Fn-integrin α5β1 to trigger autophagy in a conserved pattern in epithelial cells.
format article
author Jiachao Wang
Meiqi Meng
Miao Li
Xiaofei Guan
Jianguo Liu
Xue Gao
Qingqing Sun
Jinquan Li
Cuiqing Ma
Lin Wei
author_facet Jiachao Wang
Meiqi Meng
Miao Li
Xiaofei Guan
Jianguo Liu
Xue Gao
Qingqing Sun
Jinquan Li
Cuiqing Ma
Lin Wei
author_sort Jiachao Wang
title Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
title_short Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
title_full Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
title_fullStr Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
title_full_unstemmed Integrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A <italic toggle="yes">Streptococcus</italic> To Initiate Autophagy during Infection
title_sort integrin α5β1, as a receptor of fibronectin, binds the fbaa protein of group a <italic toggle="yes">streptococcus</italic> to initiate autophagy during infection
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/5f19651063dd419e9bfe8742dc2d0e0b
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