Polyisoprenyl phosphates in intracellular signalling

Levy, Bruce D.; Petasis, Nicos A.; Serhan, Charles N.

doi:10.1038/40180

Cited by 58 publications

(131 citation statements)

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“…Recently, the hyperimmunoglobulinemia D and periodic fever syndrome were identified as a systemic inflammatory illness stemming from partial deletion of mevalonate kinase and subsequently decreased isoprenoid production (10, 11). Together, these observations indicate that in addition to their roles as structural elements in cholesterol biosynthesis, mevalonate-derived products can also display properties of lipid mediators in inflammation.Cell activation by receptor-mediated agonists leads to rapid and transient polyisoprenyl phosphate remodeling (7,8). PSDP is present in freshly isolated human PMN.…”

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confidence: 99%

“…Polyisoprenyl phosphates, specifically the mevalonate-derived product presqualene diphosphate (PSDP), carry biological activity as an intracellular down-regulatory signal in human PMNs (7). PSDP directly inhibits phospholipase D (PLD) and leukocyte superoxide anion generation in vitro and in vivo (8,9).…”

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confidence: 99%

“…Cell activation by receptor-mediated agonists leads to rapid and transient polyisoprenyl phosphate remodeling (7,8). PSDP is present in freshly isolated human PMN.…”

mentioning

confidence: 99%

“…PSDP is present in freshly isolated human PMN. When cells are activated, PSDP shifts from perinuclear to granule and microsomal subcellular domains, and within seconds is converted to its monophosphate form, presqualene monophosphate (PSMP) (7,12). As an inhibitor of PLD and reactive oxygen species generation, PSMP is over 100-fold less potent than PSDP (8).…”

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Identification and Functional Characterization of a Presqualene Diphosphate Phosphatase

Fukunaga

Arita

Takahashi

et al. 2006

Journal of Biological Chemistry

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Neutrophil (PMN)3 activation plays a central role in diverse responses such as host defense, inflammation, and reperfusion injury (1). In response to inflammatory stimuli, PMN target reactive oxygen species and granule enzymes to phagolysosomes for microbial killing or digestion of foreign materials (2). Anomalous release of these potentially toxic agents often occurs, amplifying inflammation and leading to tissue injury, events that are implicated in a wide range of human diseases (3). To prevent an overexuberant inflammatory response and limit damage to the host, PMN programs are tightly regulated with select bioactive lipids serving as endogenous anti-inflammatory signals (4).It is now well appreciated that several enzymes of lipid metabolism also serve as signaling modules with their products acting as bioeffectors (5, 6). Polyisoprenyl phosphates, specifically the mevalonate-derived product presqualene diphosphate (PSDP), carry biological activity as an intracellular down-regulatory signal in human PMNs (7). PSDP directly inhibits phospholipase D (PLD) and leukocyte superoxide anion generation in vitro and in vivo (8,9). Recently, the hyperimmunoglobulinemia D and periodic fever syndrome were identified as a systemic inflammatory illness stemming from partial deletion of mevalonate kinase and subsequently decreased isoprenoid production (10, 11). Together, these observations indicate that in addition to their roles as structural elements in cholesterol biosynthesis, mevalonate-derived products can also display properties of lipid mediators in inflammation.Cell activation by receptor-mediated agonists leads to rapid and transient polyisoprenyl phosphate remodeling (7,8). PSDP is present in freshly isolated human PMN. When cells are activated, PSDP shifts from perinuclear to granule and microsomal subcellular domains, and within seconds is converted to its monophosphate form, presqualene monophosphate (PSMP) (7, 12). As an inhibitor of PLD and reactive oxygen species generation, PSMP is over 100-fold less potent than PSDP (8). These findings suggest the presence of a regulated diphosphate phosphatase. Here, we report the identification of the first PSDP phosphatase in human PMN and characterize its biochemical properties. EXPERIMENTAL PROCEDURESMaterials-Phosphatidic acid (PA, C10:0) and diacylglycerol pyrophosphate (DGPP, C18:1) were purchased from Avanti Polar Lipids (Alabaster, AL) and FDP from Sigma. Leukotriene B 4 was from Cayman Chemical (Ann Arbor, MI). Plasmids encoding the LPPRP2 gene were purchased from Origene (Rockville, MD). Recombinant human phosphatidic acid phosphohydrolase 2a (PAP2a), PAP2b, and PAP2c were generated as described in Ref. 13. [ 14 C]FDP (55 mCi/mmol, 50 Ci/ml) was from American Radiolabeled Chemicals (St. Louis, MO). PSDP was isolated from healthy human PMNs as described (7).Purification of PSDP Phosphatase Activity from PMN-Human PMN were isolated from whole blood as described (7), suspended (10 7 PMN/ ml) in Hanks' balanced salt solution with 1.6 mM CaCl 2 , warmed (5 min,...

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confidence: 99%

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confidence: 99%

“…Cell activation by receptor-mediated agonists leads to rapid and transient polyisoprenyl phosphate remodeling (7,8). PSDP is present in freshly isolated human PMN.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Identification and Functional Characterization of a Presqualene Diphosphate Phosphatase

Fukunaga

Arita

Takahashi

et al. 2006

Journal of Biological Chemistry

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“…presqualene diphosphate and/or squalene) can signal for HMGR degradation. Inhibition of squalene epoxidation with NB-598 may cause a buildup of presqualene diphosphate, a potent intracellular signaling molecule (63,64). Consistent with our results, Giron et al (52) have also reported that inhibition of squalene conversion to downstream sterols did not prevent MVA-mediated suppression of HMGR activity in perforated CHO cells.…”

Section: Discussionmentioning

confidence: 99%

Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

Leichner

Avner

Harats

et al. 2011

Journal of Biological Chemistry

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In mammalian cells, the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR), which catalyzes the rate-limiting step in the mevalonate pathway, is ubiquitylated and degraded by the 26 S proteasome when mevalonate-derived metabolites accumulate, representing a case of metabolically regulated endoplasmic reticulum-associated degradation (ERAD). Here, we studied which mevalonate-derived metabolites signal for HMGR degradation and the ERAD step(s) in which these metabolites are required. In HMGR-deficient UT-2 cells that stably express HMGal, a chimeric protein between ␤-galactosidase and the membrane region of HMGR, which is necessary and sufficient for the regulated ERAD, we tested inhibitors specific to different steps in the mevalonate pathway. We found that metabolites downstream of farnesyl pyrophosphate but upstream to lanosterol were highly effective in initiating ubiquitylation, dislocation, and degradation of HMGal. Similar results were observed for endogenous HMGR in cells that express this protein. Ubiquitylation, dislocation, and proteasomal degradation of HMGal were severely hampered when production of geranylgeranyl pyrophosphate was inhibited. Importantly, inhibition of protein geranylgeranylation markedly attenuated ubiquitylation and dislocation, implicating for the first time a geranylgeranylated protein(s) in the metabolically regulated ERAD of HMGR.Mammalian cells satisfy most of their cholesterol requirements through receptor-mediated endocytosis of cholesterolrich plasma lipoproteins. However, when exogenous cholesterol supply is short, or when there is an increased demand for particular nonsterol isoprenoid(s), cells up-regulate the activity of the mevalonate (MVA) 3 pathway ( Fig. 1), in which sterols and essential MVA-derived nonsterol isoprenoids are produced (1, 2). Intracellular MVA levels are finely tuned and tightly regulated by a feedback mechanism that governs the rate of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduction into MVA, the major rate-limiting step for the entire pathway (3, 4). This reaction is catalyzed by HMG-CoA reductase (HMGR), an integral glycoprotein resident to the endoplasmic reticulum (ER). Each of the 97-kDa subunits of HMGR is embedded in the ER membrane via a ϳ350 residue N-terminal noncatalytic region that spans the membrane 8 times (5-7), whereas the rest of the polypeptide faces the cytosol where it tetramerizes to form the active sites of the enzyme (5, 8, 9). To allow sufficient production of isoprenoids yet avoid overaccumulation of potentially toxic products, the activity of HMGR is stringently controlled and varies according to the cellular needs for sterol and the nonsterol products. HMGR activity increases when cells are starved for cholesterol or MVA. Conversely, abundant cholesterol and/or MVA acutely suppress the enzyme (4, 10). At the post-translational level, regulation of HMGR mainly involves modulation of its stability. Thus, in cells deprived of sterols and/or MVA, HMGR is a rather stable protein that turns over with a half-l...

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Gene profiling of inflammatory genes in day 18 endometria from pregnant and non‐pregnant mares

Patterson

Squires

Hansen

et al. 2012

Molecular Reproduction Devel

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Maternal recognition of pregnancy is a physiological process that primarily describes endometrial responses to a conceptus. Recognition of a conceptus prevents the release of prostaglandin F(2α) , thereby ensuring survival of the corpus luteum and continued progesterone production. Exactly how this occurs in the mare is poorly understood. Because prostaglandin F(2α) is a pro-inflammatory hormone, we hypothesized that differential gene expression in the endometrium at the time of maternal recognition reflects an anti-inflammatory event leading to decreased prostaglandin F(2α) secretion. Mares were inseminated, and endometrial biopsies were recovered from pregnant mares on Day 18 post-ovulation. In subsequent estrous cycles, mares were not inseminated and Day 18 post-ovulation endometrial biopsies were collected (non-pregnant control, matched per individual). Endometrial gene expression profiles were examined by screening an Affymetrix equine GeneChip containing probes specific for genes related to inflammatory processes. Microarray analysis revealed 118 genes that were up-regulated and 93 genes that were down-regulated (P < 0.001) at least 1.5-fold in the endometrium of pregnant versus non-pregnant mares. Quantitative, real-time RT-PCR confirmed the microarray results for three up-regulated genes homologous to TSC22D3, PPAPDC2, and KLF6, and three down-regulated genes homologous to ESR1, MARCKSL1, and EPSTI1 (P < 0.05). It is concluded that the presence of the equine embryo induces differential gene expression in the endometrium of Day 18 pregnant mares, and that these genes are associated with inflammatory processes and pathways involving cellular growth and proliferation. The results from this study provide important new insights into endometrial gene expression in response to early equine pregnancy.

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Polyisoprenyl phosphates in intracellular signalling

Cited by 58 publications

References 25 publications

Identification and Functional Characterization of a Presqualene Diphosphate Phosphatase

Identification and Functional Characterization of a Presqualene Diphosphate Phosphatase

Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

Gene profiling of inflammatory genes in day 18 endometria from pregnant and non‐pregnant mares

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