Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Combined Automated Annotation using Multiple IEA Methods
Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2.
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Human-cell experiments distinguish LPIN2 from LPIN1 and identify a tightly membrane-associated LPIN2 pool.
"The two lipins display distinct intracellular localization in HeLa M cells, with a pool of lipin 2 exhibiting a tight membrane association."
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LPIN2 depletion in HeLa cells triggers compensatory LPIN1 accumulation and increased total PAP1 activity, so whole-cell PAP changes do not directly measure LPIN2 catalysis in isolation.
"Small interfering RNA-mediated silencing of lipin 1 leads to a dramatic decrease of the cellular PAP1 activity in HeLa M cells, whereas silencing of lipin 2 leads to an increase of lipin 1 levels and PAP1 activity."
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Lipin-2 protein and PAP1 activity are regulated during mitosis, but the cell-cycle result is a cultured-cell context rather than a constitutive localization claim.
"Finally, we show that the PAP1 activity of both lipins is inhibited by phosphorylation during mitosis, leading to a decrease in the cellular PAP1 activity during cell division."
Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.
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Recombinant lipin-2 directly possesses phosphatidate phosphatase type-1 activity.
"Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity."
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Lipin family PAP activity is magnesium-dependent and phosphatidate-specific under the tested conditions.
"Each of the three lipin family members showed Mg2+-dependent activity that was specific for phosphatidate under the conditions employed."
Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).
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Homozygous LPIN2 mutations segregated with Majeed syndrome in the two studied families.
"Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families."
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The original human expression survey found LPIN2 broadly expressed.
"LPIN2 was found to be expressed in almost all tissues."
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This discovery study established disease causality but did not establish the inflammatory mechanism.
"The function of LPIN2 and its role in inflammation remains unknown."
A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.
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In mouse lipin-2, mutation of the serine equivalent to human Majeed variant S734L abolishes PAP activity without disrupting microsomal association.
"mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis."
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Lipin-2 can coactivate PPAR-response-element transcription, and this assay readout is separable from PAP catalysis.
"We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine."
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Tissue-expression mapping in this paper was performed in mouse and must not be represented as direct human tissue evidence.
"To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome."
Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation.
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Lipin-2 preferentially binds the dianionic form of phosphatidic acid and has a lower catalytic rate than lipin-1 in the tested biochemical system.
"We provide evidence that lipin 2, like lipin 1, binds PA via the electrostatic hydrogen bond switch mechanism but has a lower rate of catalysis."
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Unlike lipin-1, lipin-2 membrane binding and PAP activity were not negatively regulated by phosphorylation in the tested system.
"Importantly, phosphorylation of lipin 2 does not negatively regulate either membrane binding or PAP activity."
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The study directly notes that earlier relative activity measurements used human lipin-2 in cell lysates, while its own localization experiments include mouse 3T3-L1 adipocytes.
"The relative PAP activity of human lipin 2 has been previously determined in cell lysates ( 17 , 18 )."
Lipin proteins form homo- and hetero-oligomers.
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Lipin-1 formed stable hetero-oligomers with lipin-2 and lipin-3 in the study's interaction systems.
"In the present study, using various approaches, we revealed that lipin 1 formed stable homo-oligomers with itself and hetero-oligomers with lipin 2/3."
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The paper's phrase “mammalian lipin isoforms” refers to the LPIN1/LPIN2/LPIN3 family members, not splice isoforms of LPIN2.
"The present study provides evidence that lipin proteins function as oligomeric complexes and that the three mammalian lipin isoforms can form combinatorial units."
Lipin-2 reduces proinflammatory signaling induced by saturated fatty acids in macrophages.
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LPIN2 depletion enhances saturated-fatty-acid-driven inflammatory gene expression through JNK1/c-Jun in murine and human macrophage systems.
"Depletion of lipin-2 promotes the increased expression of the proinflammatory genes Il6, Ccl2, and Tnfα, which depends on the overstimulation of the JNK1/c-Jun pathway by saturated fatty acids."
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LPIN2 loss reduces triacylglycerol content specifically in saturated-fatty-acid-overloaded macrophages.
"Metabolically, the absence of lipin-2 reduces the cellular content of triacylglycerol in saturated fatty acid-overloaded macrophages."
Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation.
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LPIN2 restrains excessive IL-1β production in primary human and mouse macrophages through inflammasome priming and activation mechanisms.
"We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3."
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LPIN2 loss lowers macrophage cholesterol, and cholesterol restoration attenuates P2X7 currents and downstream IL-1β-generating events.
"In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production."
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LPIN2-dependent cellular cholesterol levels modulate P2X7/NLRP3 signaling.
"Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels."
Lipin-2 degradation elicits a proinflammatory gene signature in macrophages.
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β-TRCP binds LPIN2 and promotes its ubiquitination and proteasomal degradation.
"Here, we demonstrate that Lipin-2 interacts with β-TRCP, a substrate receptor subunit of the SCFβ-TRCP E3 ligase, and undergoes ubiquitination and proteasomal degradation."
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β-TRCP knockout caused LPIN2 accumulation and suppressed LPS-induced inflammatory signaling in a mouse macrophage cell line.
"β-TRCP-knockout in RAW264.7 macrophages resulted in Lipin-2 accumulation, leading to the suppression of LPS-induced MAPK activation and subsequent proinflammatory gene expression."
Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum.
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Mouse Lpin2 deficiency induces tissue-specific compensatory Lpin1 and reveals hepatic and cerebellar lipid-homeostasis roles.
"By using lipin-2-deficient mice, we uncovered a functional relationship between lipin-1 and lipin-2 that operates in a tissue-specific and age-dependent manner."
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The mouse model recapitulates anemia but not osteomyelitis, limiting direct transfer of its disease physiology to human Majeed syndrome.
"Similar to patients with Majeed syndrome, lipin-2-deficient mice developed anemia, but did not show evidence of osteomyelitis, suggesting that additional environmental or genetic components contribute to the bone abnormalities observed in patients."
Lipin-2 regulates the antiviral and anti-inflammatory responses to interferon.
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Interferon induces Lpin2 through STAT1-dependent regulation in the experimental macrophage systems.
"Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner."
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LPIN2 depletion in primary human macrophages augments IL1B expression after extracellular poly(I:C) stimulation.
"Importantly, the same behavior was also found in LPIN2–silenced primary human macrophages (Fig 5C)."
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The COVID-19 observation is an expression-severity correlation, not direct causal evidence for LPIN2 in patients.
"Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease."
PA is dephosphorylated to DAG by LPIN
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Reactome places LPIN1-3-mediated PA-to-DAG conversion at the human ER membrane.
"At the endoplasmic reticulum (ER) membrane, phosphatidate phosphatase 1-3 (LPIN) dephosphorylates phosphatidic acid (PA) to form diacylglycerol (DAG) (Grimsey et al. 2008, Donkor et al. 2007)."
Triglyceride biosynthesis
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Reactome places PA-to-DAG conversion within the four-part human triacylglycerol-biosynthesis pathway.
"The overall process of triglyceride (triacylglycerol) biosynthesis consists of four biochemical pathways: fatty acyl-CoA biosynthesis, conversion of fatty acyl-CoA to phosphatidic acid, conversion of phosphatidic acid to diacylglycerol, and conversion of diacylglycerol to triacylglycerol."
1,2-diacyl-glycerol 3-phosphate + H2O => 1,2-diacyl-glycerol + orthophosphate
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Reactome identifies human LPIN2 as experimentally supported for phosphatidate hydrolysis to DAG and orthophosphate.
"The activities of LPIN1 and LPIN2 have been established experimentally (Grimsey et al. 2008); that of LPIN3 is inferred from its structural similarities both to its human paralogues and to its mouse ortholog (Donkor et al. 2007)."
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Reactome distinguishes stable ER association evidence for LPIN1 from inferred catalytic activity at that site for the other lipins.
"Only LPIN1 has been shown to be stably associated with the endoplasmic reticulum, but all three enzymes appear to be catalytically active at that location (Grimsey et al. 2008; Donkor et al. 2007)."