Ceramide in the eukaryotic stress response

Hannun, Yusuf A.; Luberto, Chiara

doi:10.1016/s0962-8924(99)01694-3

Cited by 700 publications

(378 citation statements)

References 55 publications

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“…These enzymes catalyze the breakdown of sphingomyelin to ceramide and phosphocholine (Goni & Alonso, 2002). Interestingly, neutral sphingomyelinase (NSM) and ASM are activated in response to various stress stimuli, including hydrogen peroxide, hypoxia, TNF‐α, and infection (Hannun & Luberto, 2000; Grassme et al , 2003; Marchesini & Hannun, 2004). …”

Section: Resultsmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of Shigella flexneri to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of Shigella binding to host cells. Interestingly, stress caused by intracellular Shigella replication also results in remodeling of the host cell membrane, in vitro and in vivo, which precludes re‐infection by this and other non‐motile pathogens. In contrast, Salmonella Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens.

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Section: Resultsmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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“…Addition of cellpermeable synthetic short chain ceramides closely mimics apoptosis-inducing stimuli, and elevation of endogenous ceramide has been described as a hallmark of the apoptotic death program (10,12,35). There are several studies documenting necessary roles for ceramide in regulating various aspects of apoptosis.…”

Section: Fig 4 Ceramide Subspecies Analysis By Tandem Mass Spectrommentioning

confidence: 99%

Induction of Apoptosis through B-cell Receptor Cross-linking Occurs via de Novo Generated C16-Ceramide and Involves Mitochondria

Kroesen¹,

Pettus²,

Luberto³

et al. 2001

Journal of Biological Chemistry

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151

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B-cells, triggered via their surface B-cell receptor (BcR), start an apoptotic program known as activationinduced cell death (AICD), and it is widely believed that this phenomenon plays a role in the restriction and focusing of the immune response. Although both ceramide and caspases have been proposed to be involved in AICD, the contribution of either and the exact molecular events through which AICD commences are still unknown. Here we show that in Ramos B-cells, BcR-triggered cell death is associated with an early rise of C16 ceramide that derives from activation of the de novo pathway, as demonstrated using a specific inhibitor of ceramide synthase, fumonisin B1 (FB1), and using pulse labeling with the metabolic sphingolipid precursor, palmitate. There was no evidence for activation of sphingomyelinases or hydrolysis of sphingomyelin. Importantly, FB1 inhibited several specific apoptotic hallmarks such as poly(A)DP-ribose polymerase cleavage and DNA fragmentation. Electron microscopy revealed morphological evidence of mitochondrial damage, suggesting the involvement of mitochondria in BcR-triggered apoptosis, and this was inhibited by FB1. Moreover, a loss of mitochondrial membrane potential was observed in Ramos cells after BcR cross-linking, which was inhibited by the addition of FB1. Interestingly, benzyloxycarbonyl-Val-Ala-DL-Asp, a broad spectrum caspase inhibitor did not inhibit BcR-induced mitochondrial membrane permeability transition but did block DNA fragmentation. These results suggest a crucial role for de novo generated C16 ceramide in the execution of AICD, and they further suggest an ordered and more specific sequence of biochemical events in which de novo generated C16 ceramide is involved in mitochondrial damage resulting in a downstream activation of caspases and apoptosis.

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“…Hydrolysis of sphingomyelin (SM) by sphingomyelinases (SMases), with the subsequent generation of ceramide, is a signalling pathway implicated in a number of cellular responses (1)(2)(3). Ceramide has been suggested to play important roles in cell cycle arrest, apoptosis, inflammation and the regulation of the eukaryotic stress response.…”

Section: Introductionmentioning

confidence: 99%

“…Ceramide has been suggested to play important roles in cell cycle arrest, apoptosis, inflammation and the regulation of the eukaryotic stress response. Although ceramide can be generated by de novo synthesis through ceramide-synthase, for the majority of cellular responses it is generated from sphingomyelin by the action of neutral or acidic sphingomyelinases (1)(2)(3). These enzymes are sphingomyelin-specific phosphodiesterases that hydrolyze the phosphodiester bond of sphingomyelin yielding ceramide and phosphocholine.…”

Section: Introductionmentioning

confidence: 99%

Structural Requirements for Catalysis and Membrane Targeting of Mammalian Enzymes with Neutral Sphingomyelinase and Lysophospholipid Phospholipase C Activities

Rodrigues‐Lima

Fensome²,

Josephs³

et al. 2000

Journal of Biological Chemistry

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The sequence similarity with bacterial neutral sphingomyelinase (NSM) resulted in the isolation of putative mammalian counterparts and, subsequently, identification of similar molecules in a number of other eukaryotic organisms. Based on sequence similarities and previous characterization of the mammalian enzymes, we have chemically modified specific residues and performed site directed mutagenesis in order to identify critical catalytic residues and determinants for membrane localization. Modification of histidine residues and the substrate protection experiments demonstrated the presence of reactive histidine residues within the active site. Site directed mutagenesis suggested an essential role in catalysis for two histidine residues (His136 and His272) which are conserved in all sequences. Mutations of two additional histidines (His138 and His151), conserved only in eukaryotes, resulted in reduced NSM activity. In addition to sphingomyelin, the enzyme also hydrolyzed lysophosphatidylcholine.Exposure to an oxidizing environment or modification of cysteine residues using several specific compounds also inactivated the enzyme. Site-directed mutagenesis of eight cysteine residues and gel-shift analysis demonstrated that these residues did not participate in the catalytic reaction and suggested the involvement of cysteines in the formation/breakage of disulfide bonds which could underlie the reversible inactivation by the oxidizing compounds.Cellular localization studies of a series of deletion mutants expressed as GFP-fusion proteins, demonstrated that the transmembrane region contains determinants for the ER localization.by guest on

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Ceramide in the eukaryotic stress response

Cited by 700 publications

References 55 publications

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

Induction of Apoptosis through B-cell Receptor Cross-linking Occurs via de Novo Generated C16-Ceramide and Involves Mitochondria

Structural Requirements for Catalysis and Membrane Targeting of Mammalian Enzymes with Neutral Sphingomyelinase and Lysophospholipid Phospholipase C Activities

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