Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

Sanman, Laura E.; Q, Yu; Eisele, Nicholas A.; Ng, Tessie M; Linden, Wouter A. van der; Monack, Denise M.; Weerapana, Eranthie; Bogyo, Matthew

doi:10.7554/elife.13663

Cited by 161 publications

(183 citation statements)

References 52 publications

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“…Thus PrkA is likely to be crucial for matching energy intake and expenditure of the cell. Intracellular pathogens have evolved specific metabolic strategies to avoid disruption of host glycolysis to avoid innate immune detection and maintain their replicative niche [94]. Therefore, the regulation of central metabolism by PrkA could be considered an essential virulence factor.…”

Section: Discussionmentioning

confidence: 99%

The Listeria monocytogenes PASTA Kinase PrkA and Its Substrate YvcK Are Required for Cell Wall Homeostasis, Metabolism, and Virulence

et al. 2016

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Obstacles to bacterial survival and replication in the cytosol of host cells, and the mechanisms used by bacterial pathogens to adapt to this niche are not well understood. Listeria monocytogenes is a well-studied Gram-positive foodborne pathogen that has evolved to invade and replicate within the host cell cytosol; yet the mechanisms by which it senses and responds to stress to survive in the cytosol are largely unknown. To assess the role of the L. monocytogenes penicillin-binding-protein and serine/threonine associated (PASTA) kinase PrkA in stress responses, cytosolic survival and virulence, we constructed a ΔprkA deletion mutant. PrkA was required for resistance to cell wall stress, growth on cytosolic carbon sources, intracellular replication, cytosolic survival, inflammasome avoidance and ultimately virulence in a murine model of Listeriosis. In Bacillus subtilis and Mycobacterium tuberculosis, homologues of PrkA phosphorylate a highly conserved protein of unknown function, YvcK. We found that, similar to PrkA, YvcK is also required for cell wall stress responses, metabolism of glycerol, cytosolic survival, inflammasome avoidance and virulence. We further demonstrate that similar to other organisms, YvcK is directly phosphorylated by PrkA, although the specific site(s) of phosphorylation are not highly conserved. Finally, analysis of phosphoablative and phosphomimetic mutants of YvcK in vitro and in vivo demonstrate that while phosphorylation of YvcK is irrelevant to metabolism and cell wall stress responses, surprisingly, a phosphomimetic, nonreversible negative charge of YvcK is detrimental to cytosolic survival and virulence in vivo. Taken together our data identify two novel virulence factors essential for cytosolic survival and virulence of L. monocytogenes. Furthermore, our data demonstrate that regulation of YvcK phosphorylation is tightly controlled and is critical for virulence. Finally, our data suggest that yet to be identified substrates of PrkA are essential for cytosolic survival and virulence of L. monocytogenes and illustrate the importance of studying protein phosphorylation in the context of infection.

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Section: Discussionmentioning

confidence: 99%

The Listeria monocytogenes PASTA Kinase PrkA and Its Substrate YvcK Are Required for Cell Wall Homeostasis, Metabolism, and Virulence

et al. 2016

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“…2, 3 Other studies demonstrate that disruption of glycolytic flux is detrimental to cells, and leads to inflammasome activation and pyroptosis in macrophages. 4 …”

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confidence: 99%

Does Elevated Glucose Promote Atherosclerosis? Pros and Cons

Bornfeldt

2016

Circulation Research

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“…Additionally, these results provide further evidence of what Olive and Sassetti (52) describe as a pathogen’s ability to “sense the metabolic environment of the host, adapting to changing nutrient availability.” Further, these phosphorylation alterations at the gut level during the first 3 weeks after infection of day-old broilers with ST appear to lead to key metabolic changes that affected fatty acid and glucose metabolism through the 5′-AMPK and the insulin/mTOR signaling pathway in the skeletal muscle were altered (53). Supplemental proof for the effects of fatty acid and glucose metabolism on long-term persistence of Salmonella was recently demonstrated using the murine macrophage model (54, 55). ST preferred living in alternatively activated macrophages that require the activation of the transcription factor, peroxisome proliferator-activating receptor δ (PPARδ), which regulates fatty acid metabolism (54).…”

Section: Stage 2 Disease Tolerancementioning

confidence: 99%

Immunometabolic Phenotype Alterations Associated with the Induction of Disease Tolerance and Persistent Asymptomatic Infection of Salmonella in the Chicken Intestine

Kogut

Arsenault

2017

Front. Immunol.

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The adaptation of Salmonella enterica to the eukaryotic host is a key process that enables the bacterium to survive in a hostile environment. Salmonella have evolved an intimate relationship with its host that extends to their cellular and molecular levels. Colonization, invasion, and replication of the bacteria in an appropriate host suggest that modification of host functions is central to pathogenesis. Intuitively, this subversion of the cell must be a complex process, since hosts are not inherently programmed to provide an environment conducive to pathogens. Hosts have evolved countermeasures to pathogen invasion, establishment, and replication through two types of defenses: resistance and tolerance. Resistance functions to control pathogen invasion and reduce or eliminate the invading pathogen. Research has primarily concentrated on resistance mechanisms that are mediated by the immune system. On the other hand, tolerance is mediated by different mechanisms that limit the damage caused by a pathogen’s growth without affecting or reducing pathogen numbers or loads. The mechanisms of tolerance appear to be separated into those that protect host tissues from the virulence factors of a pathogen and those that limit or reduce the damage caused by the host immune and inflammatory responses to the pathogen. Some pathogens, such as Salmonella, have evolved the capacity to survive the initial robust immune response and persist. The persistent phase of a Salmonella infection in the avian host usually involves a complex balance of protective immunity and immunopathology. Salmonella is able to stay in the avian ceca for months without triggering clinical signs. Chronic colonization of the intestinal tract is an important aspect of persistent Salmonella infection because it results in a silent propagation of bacteria in poultry stocks due to the impossibility to isolate contaminated animals. Data from our lab promote the hypothesis that Salmonella have evolved a unique survival strategy in poultry that minimizes host defenses (disease resistance) during the initial infection and then exploits and/or induces a dramatic immunometabolic reprogramming in the cecum that alters the host defense to disease tolerance. Unfortunately, this disease tolerance results in the ongoing human food safety dilemma.

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Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

Cited by 161 publications

References 52 publications

The Listeria monocytogenes PASTA Kinase PrkA and Its Substrate YvcK Are Required for Cell Wall Homeostasis, Metabolism, and Virulence

The Listeria monocytogenes PASTA Kinase PrkA and Its Substrate YvcK Are Required for Cell Wall Homeostasis, Metabolism, and Virulence

Does Elevated Glucose Promote Atherosclerosis? Pros and Cons

Immunometabolic Phenotype Alterations Associated with the Induction of Disease Tolerance and Persistent Asymptomatic Infection of Salmonella in the Chicken Intestine

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