title: Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy.
abstract: Intracellular pathogens like Shigella flexneri enter host cells by phagocytosis. Once inside, the pathogen breaks the vacuolar membrane for cytosolic access. The fate and function of the vacuolar membrane remnants are not clear. Examining Shigella-infected nonmyeloid cells, we observed that proteins associated with vacuolar membrane remnants are polyubiquinated, recruit the autophagy marker LC3 and adaptor p62, and are targeted to autophagic degradation. Further, inflammasome components and caspase-1 were localized to these membranes and correlated with dampened inflammatory response and necrotic cell death. In Atg4B mutant cells in which autophagosome maturation is blocked, polyubiquitinated proteins and P62 accumulated on membrane remnants, and as in autophagy-deficient Atg5(-/-) cells, the early inflammatory and cytokine response was exacerbated. Our results suggest that host membranes, after rupture by an invading cytoplasm-targeted bacterium, contribute to the cellular responses to infection by acting as a signaling node, with autophagy playing a central role in regulating these responses.
authors.affiliation: Cellular Microbiology and Infectious Pathogeny UMR8161 (CNRS), 1 rue du Prof. Calmette, F-59021 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupont
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: Julie
authors.initials: J
authors.lastname: Bertout
authors.forename: Irit
authors.initials: I
authors.lastname: Paz
authors.forename: Barbara
authors.initials: B
authors.lastname: Freche
authors.forename: Guy Tran
authors.initials: GT
authors.lastname: Van Nhieu
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Frank
authors.initials: F
authors.lastname: Lafont
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D001343:Autophagy; D020170:Caspase 1 / Q000032:analysis; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000032:analysis; D010588:Phagosomes / Q000382:microbiology*; D000071456:Sequestosome-1 Protein; D012763:Shigella flexneri / Q000472:pathogenicity*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D020170:Caspase 1