Autophagy Proteins Promote Repair of Endosomal Membranes Damaged by the Salmonella Type Three Secretion System 1

Kreibich, Saskia; Emmenlauer, Mario; Fredlund, Jennifer; Rämö, Pauli; Münz, Christian; Dehio, Christoph; Enninga, Jost; Hardt, Wolf‐Dietrich

doi:10.1016/j.chom.2015.10.015

Cited by 119 publications

(133 citation statements)

References 72 publications

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“…A recent report provides evidence for a second role of autophagy in mediating sealing of the SCV membrane damaged by activity of the SPI1-T3SS, a phenomenon required for subsequent induction of the SPI2-T3SS. 33 Since we observed aggrephagy at the same extent in cells infected with wild-type and SPI1D strains (Fig. 7) and SPI2-T3SS is required for the formation of the LGP C aggresome (Fig.…”

Section: Discussionmentioning

confidence: 63%

“…A recent report provided evidence for a role of autophagy in repairing some damaged phagosomes harboring S. Typhimurium. 33 Another study, however, showed that S. Typhimurium subverts autophagy to proliferate in the cytosol of epithelial cells. 19 The precise contribution of autophagy to the balance of the intraphagosomal and cytosolic bacterial populations coexisting in the epithelial cell remains not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular Salmonella induces aggrephagy of host endomembranes in persistent infections

et al. 2016

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Xenophagy has been studied in epithelial cells infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). Distinct autophagy receptors target this pathogen to degradation after interacting with ubiquitin on the surface of cytosolic bacteria, and the phagophore-and autophagosome-associated protein MAP1LC3/LC3. Glycans exposed in damaged phagosomal membranes and diacylglycerol accumulation in the phagosomal membrane also trigger S. Typhimurium xenophagy. How these responses control intraphagosomal and cytosolic bacteria remains poorly understood. Here, we examined S. Typhimurium interaction with autophagy in fibroblasts, in which the pathogen displays limited growth and does not escape into the cytosol. Live-cell imaging microscopy revealed that S. Typhimurium recruits late endosomal or lysosomal compartments that evolve into a membranous aggregate connected to the phagosome. Active dynamics and integrity of the phagosomal membrane are requisite to induce such aggregates. This membranous structure increases over time to become an aggresome that engages autophagy machinery at late infection times (> 6 h postentry). The newly formed autophagosome harbors LC3 and the autophagy receptor SQSTM1/p62 but is devoid of ubiquitin and the receptor CALCOCO2/NDP52. Live-cell imaging showed that this autophagosome captures and digests within the same vacuole the aggresome and some apposed intraphagosomal bacteria. Other phagosomes move away from the aggresome and avoid destruction. Thus, host endomembrane accumulation resulting from activity of intracellular S. Typhimurium stimulates a novel type of aggrephagy that acts independently of ubiquitin and CALCOCO2, and destroys only a few bacteria. Such selective degradation might allow the pathogen to reduce its progeny and, as a consequence, to establish persistent infections.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Intracellular Salmonella induces aggrephagy of host endomembranes in persistent infections

et al. 2016

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“…This enhanced state of autophagy likely contributes to the increased capacity of the MTMR4-depleted cells to eliminate intracellular Salmonella . Recent studies have made conflicting conclusions about the role of autophagy with regards to the intracellular viability of Salmonella (Yu et al, 2014; Kreibich et al, 2015). Using CFU assays to monitored viable bacteria 6 h post-infection, Yu et al (2014) observed decreased viability in HeLa cells when autophagy was inhibited using RNAi-depletion of LC3 while Kreibich et al (2015) observed elevated viable bacteria in autophagy impaired Atg5−/− MEFs.…”

Section: Discussionmentioning

confidence: 99%

MTMR4 Is Required for the Stability of the Salmonella-Containing Vacuole

Teo

Kerr

Teasdale

2016

Front. Cell. Infect. Microbiol.

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The intracellular pathogen Salmonella enterica servovar Typhimurium (S.typhimurium) modulates the host cell's phosphoinositide (PI) metabolism to establish its intracellular replicative niche, the Salmonella-containing vacuole (SCV). Upon invasion, phosphoinositide 3-phosphate (PI(3)P) and other early endosomal markers are rapidly recruited to and remain associated with the SCV throughout its early maturation. While the phosphoinositide 3-phosphatase myotubularin 4 (MTMR4) has an established role in regulating autophagy and cellular PI(3)P-content, two processes associated with the intracellular survival of S. typhimurium, a direct role for MTMR4 in Salmonella biology has not been examined. Here we demonstrate that GFP-tagged MTMR4 is recruited to the SCV and infection of cells depleted of endogenous MTMR4 results in a decrease in viable intracellular Salmonella. This reflects a significant increase in the proportion of SCVs with compromised integrity, which targets the compartment for autophagy and consequent bacterial cell death. These findings highlight the importance of PI(3)P regulation to the integrity of the SCV and reveal a novel role for the myotubularins in bacterial pathogenesis.

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“…These signals recruit essential anti-bacterial autophagy components including several cargo receptors, the kinase TBK1 and WIPI2, that restrict Salmonella proliferation (Radtke et al, 2007;Thurston et al, 2016Thurston et al, , 2009Thurston et al, , 2012. Autophagy has also a role in sealing damaged endosomal membranes, allowing T3SS2 induction inside the SCV (Kreibich et al, 2015;Owen and Casanova, 2015). In epithelial cells, Salmonella induces the formation of ubiquitinated aggregates near the SCV in a T3SS2-dependent manner.…”

Section: Autophagymentioning

confidence: 99%