title: Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis.
abstract: Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.|Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.|Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Sisi
authors.initials: S
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.|Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Xikun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Shirui
authors.initials: S
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.|Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Rongpeng
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.|Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jundt
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Alec
authors.initials: A
authors.lastname: Hidebrand
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Inflammations & Allergic Diseases Research Unit, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, P.R. China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P.R. China.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D004195:Disease Models, Animal; D019084:Fluorescent Antibody Technique, Indirect; D006790:Host-Parasite Interactions / Q000276:immunology*; D015151:Immunoblotting; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa; D060888:Real-Time Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D019061:src-Family Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C471359:LAB protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases