Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy.
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.
Dupont
Nicolas
N
Cellular Microbiology and Infectious Pathogeny UMR8161 (CNRS), 1 rue du Prof. Calmette, F-59021 Lille, France.
Lacas-Gervais
Sandra
S
Bertout
Julie
J
Paz
Irit
I
Freche
Barbara
B
Van Nhieu
Guy Tran
GT
van der Goot
F Gisou
FG
Sansonetti
Philippe J
PJ
Lafont
Frank
F
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
D048868:Adaptor Proteins, Signal Transducing; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D020170:Caspase 1