Bcl-xL Affects Group A Streptococcus-Induced Autophagy Directly, by Inhibiting Fusion between Autophagosomes and Lysosomes, and Indirectly, by Inhibiting Bacterial Internalization via Interaction with Beclin 1-UVRAG.
Bcl-xL Affects Group A Streptococcus-Induced Autophagy Directly, by Inhibiting Fusion between Autophagosomes and Lysosomes, and Indirectly, by Inhibiting Bacterial Internalization via Interaction with Beclin 1-UVRAG.
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DOI：
10.1371/journal.pone.0170138
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Nakagawa I
中科院分区：
文献类型：
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作者：
Nakajima S;Aikawa C;Nozawa T;Minowa-Nozawa A;Toh H;Nakagawa I
抗凋亡Bcl-2和Bcl-xL被提出通过直接与Beclin 1相互作用来调节饥饿诱导的自噬。Beclin 1也被认为参与多种囊泡运输途径，如通过与Atg 14 L和UVRAG结合的内吞作用。然而，Bcl-2家族蛋白和Beclin 1的相互作用如何调节抗细菌自噬（xenophagy）仍不清楚。在这项研究中，我们分析了这些相互作用使用A组链球菌（GAS;化脓性链球菌）感染作为一个模型。GAS通过内吞作用内化到上皮细胞中，而GAS的细胞内命运是通过自噬降解。在这里，我们发现Bcl-xL而不是Bcl-2调节GAS诱导的自噬。在Bcl-xL基因敲除细胞中，GAS感染过程中自噬体-溶酶体融合和内化过程被促进。此外，Beclin 1的敲除表型模仿了GAS的内化缺陷。此外，UVRAG不仅与Beclin 1相互作用，而且与Bcl-xL相互作用，并且UVRAG的过表达部分地挽救了Beclin 1敲除细胞在GAS感染期间的内化缺陷。因此，我们的研究结果表明，Bcl-xL抑制气体诱导的自噬直接通过抑制自噬体-溶酶体融合和间接通过抑制GAS内化通过与Beclin 1-UVRAG的相互作用。
Anti-apoptotic Bcl-2 and Bcl-xL are proposed to regulate starvation-induced autophagy by directly interacting with Beclin 1. Beclin 1 is also thought to be involved in multiple vesicle trafficking pathways such as endocytosis by binding to Atg14L and UVRAG. However, how the interaction of Bcl-2 family proteins and Beclin 1 regulates anti-bacterial autophagy (xenophagy) is still unclear. In this study, we analyzed these interactions using Group A Streptococcus (GAS; Streptococcus pyogenes) infection as a model. GAS is internalized into epithelial cells through endocytosis, while the intracellular fate of GAS is degradation by autophagy. Here, we found that Bcl-xL but not Bcl-2 regulates GAS-induced autophagy. Autophagosome-lysosome fusion and the internalization process during GAS infection were promoted in Bcl-xL knockout cells. In addition, knockout of Beclin 1 phenocopied the internalization defect of GAS. Furthermore, UVRAG interacts not only with Beclin 1 but also with Bcl-xL, and overexpression of UVRAG partially rescued the internalization defect of Beclin 1 knockout cells during GAS infection. Thus, our results indicate that Bcl-xL inhibits GAS-induced autophagy directly by suppressing autophagosome-lysosome fusion and indirectly by suppressing GAS internalization via interaction with Beclin 1-UVRAG.