StreptococcusIntegrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A To Initiate Autophagy during Infection.
StreptococcusIntegrin α5β1, as a Receptor of Fibronectin, Binds the FbaA Protein of Group A To Initiate Autophagy during Infection.
复制标题
整合素α5β1作为纤连蛋白的受体，与A组链球菌的FbaA蛋白结合，在感染过程中启动自噬
作者：
Wang J;Meng M;Li M;Guan X;Liu J;Gao X;Sun Q;Li J;Ma C;Wei L
AStreptococcus（GAS）是最常见的细胞外病原体之一，已报道侵袭上皮细胞和内皮细胞。结果表明，M1 GAS菌株SF370可被呼吸道上皮细胞有效清除。新的证据表明，自噬是非吞噬细胞消灭胞内细菌的重要策略。在病原体识别后，细胞表面受体可以直接触发自噬，这是控制感染的关键步骤。然而，细胞如何感知入侵细菌并利用这些信息特异性地触发自噬的机制尚不清楚。在本研究中，我们用M1 GAS菌株SF370的M和FbaA突变体或纯化的M和FbaA蛋白（GAS的两个关键表面结构蛋白）刺激细胞和感染小鼠，发现只有FbaA蛋白参与自噬诱导。此外，FbaA蛋白诱导自噬独立于常见的模式识别受体（如toll样受体）；相反，它依赖于与细胞表面表达的整合素α5β1的结合，这是由细胞外基质蛋白纤维连接蛋白（Fn）介导的。FbaA-Fn-integrin α5β1复合物通过mTOR-ULK1-Beclin-1通路激活Beclin-1，使Beclin-1/Vps34复合物募集Rab7，最终促进自噬体的形成。通过敲除Hep2细胞中的整合素α5β1、Fn、Atg5、Beclin-1和ULK1，并在小鼠中敲除Atg5或整合素α5β1，我们揭示了整合素α5β1在诱导自噬中的新作用。我们的研究表明，整合素α5β1通过与病原体成分的相互作用，启动有效的宿主先天免疫来对抗入侵的细胞内病原体。自噬通常被认为是先天免疫系统通过捕获并将其转移到溶酶体来消除侵入性病原体的一种策略。目前，研究人员更多关注的是由GAS分泌的毒力因子如何调控自噬过程。本研究首次证明了M1 GAS菌株SF370的结构蛋白FbaA是上皮细胞自噬的有效诱导剂。此外，我们发现上皮细胞中的整合素α5β1作为受体，通过Fn与M1 GAS菌株SF370的FbaA结合，启动诱导自噬的信号传导。我们的研究揭示了病原体诱导fn -整合素α5β1以保守模式触发上皮细胞自噬的潜在机制。
Group AStreptococcus(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.IMPORTANCEAutophagy 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 cellsin vitroandin vivoacts 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.