title: 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.
abstract: 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.
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Shintaro
authors.identifier: http://orcid.org/0000-0003-4858-3391
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Aikawa
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Minowa-Nozawa
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Toh
authors.affiliation: Department of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakagawa
mesh_terms: D017209:Apoptosis; D000071182:Autophagosomes / Q000648:ultrastructure; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000502:physiology* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013297:Streptococcus pyogenes / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D051020:bcl-X Protein