Corrigendum: Macrophage SREBP1 regulates skeletal muscle regeneration.

[This corrects the article DOI: 10.3389/fimmu.2023.1251784.].

Group III secreted phospholipase A2 -driven lysophospholipid pathway protects against allergic asthma.

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2 s (PLA2 s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA2 (sPLA2 -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2 -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 (LPA2 ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2 -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2 -III-LPA pathway may be a new therapeutic target for allergic asthma.

1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (TH17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of TH17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in TH17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient TH17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of TH17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced TH17 cell differentiation and the pathogenicity of TH17 cells.

PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke.

The brain is generally resistant to regeneration after damage. The cerebral endogenous mechanisms triggering brain self-recovery have remained unclarified to date. We here discovered that the secreted phospholipase PLA2G2E from peri-infarct neurons generated dihomo-γ-linolenic acid (DGLA) as necessary for triggering brain-autonomous neural repair after ischemic brain injury. Pla2g2e deficiency diminished the expression of peptidyl arginine deiminase 4 (Padi4), a global transcriptional regulator in peri-infarct neurons. Single-cell RNA sequencing (scRNA-seq) and epigenetic analysis demonstrated that neuronal PADI4 had the potential for the transcriptional activation of genes associated with recovery processes after ischemic stroke through histone citrullination. Among various DGLA metabolites, we identified 15-hydroxy-eicosatrienoic acid (15-HETrE) as the cerebral metabolite that induced PADI4 in peri-infarct-surviving neurons. Administration of 15-HETrE enhanced functional recovery after ischemic stroke. Thus, our research clarifies the promising potential of brain-autonomous neural repair triggered by the specialized lipids that initiate self-recovery processes after brain injury.

Modulation of immunity by the secreted phospholipase A2 family.

Among the phospholipase A2 (PLA2 ) superfamily, which typically catalyzes the sn-2 hydrolysis of phospholipids to yield fatty acids and lysophospholipids, the secreted PLA2 (sPLA2 ) family contains 11 isoforms in mammals. Individual sPLA2 s have unique enzymatic specificity toward fatty acids and polar heads of phospholipid substrates and display distinct tissue/cellular distributions, suggesting their distinct physiological functions. Recent studies using knockout and/or transgenic mice for a full set of sPLA2 s have revealed their roles in modulation of immunity and related disorders. Application of mass spectrometric lipidomics to these mice has enabled to identify target substrates and products of individual sPLA2 s in given tissue microenvironments. sPLA2 s hydrolyze not only phospholipids in the plasma membrane of activated, damaged or dying mammalian cells, but also extracellular phospholipids such as those in extracellular vesicles, microbe membranes, lipoproteins, surfactants, and dietary phospholipids, thereby exacerbating or ameliorating various diseases. The actions of sPLA2 s are dependent on, or independent of, the generation of fatty acid- or lysophospholipid-derived lipid mediators according to the pathophysiological contexts. In this review, we make an overview of our current understanding of the roles of individual sPLA2 s in various immune responses and associated diseases.

The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism.

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism.

Organism-Wide Analysis of Sepsis Reveals Mechanisms of Systemic Inflammation.

Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the impact of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of the effects of sepsis across tissues. These data revealed two interorgan mechanisms key in sepsis. First, we discover a simplifying principle in the systemic behavior of the cytokine network during sepsis, whereby a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1ß explains half of all the cellular effects of sepsis on 195 cell types across 9 organs. Second, we find that the secreted phospholipase PLA2G5 mediates hemolysis in blood, contributing to organ failure during sepsis. These results provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the body.

Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups.

Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.

Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking.

BACKGROUND: Although hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells. METHODS: This study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice. RESULTS: Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid, accumulated in the lymphatic environment. Lysophosphatidic acid enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering Th1/Th2 (T helper type1/2) subsets. This occurs via the proteolytic degradation of MEKK1 (mitogen-activated protein kinase kinase kinase 1) and the subsequent inhibition of TGF (transforming growth factor)-ß1 production in LECs. Targeting calpain systems in LECs expanded Tregs in the blood circulation and reduced aortic atherosclerosis in hypercholesterolemic mice, concomitant with the reduction of proinflammatory macrophages in the lesions. Treg expansion in the blood circulation and atheroprotection in calpain-targeted mice was prevented by the administration of TGF-ß type-I receptor inhibitor. Moreover, lysophosphatidic acid-induced calpain overactivation potentiated the IL (interleukin)-18/NF-κB (nuclear factor κB)/VCAM1 (vascular cell adhesion molecule 1) axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Indeed, VCAM1 in LECs was upregulated in hypercholesterolemic mice and human cases of coronary artery disease. Neutralization of VCAM1 or targeting LEC calpain systems recovered afferent Treg transportation via lymphatic vessels in mice. CONCLUSIONS: Calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.

Macrophage SREBP1 regulates skeletal muscle regeneration.

Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of Srebf1, encoding SREBP1, or macrophage-specific deletion of Srebf1a, encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. Srebf1 deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in Srebf1 -/- muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair.

Lipid profiling reveals the presence of unique lipid mediators in human milk from healthy and mastitic subjects.

Milk lipids are an important energy source for infants, but the composition of milk lipids has not yet been clarified in detail. In this study, we analyzed free fatty acids and their metabolites in milk from humans and cows. In comparison to cow milk, human milk showed a higher content of free fatty acids including polyunsaturated fatty acids, especially ω-3 fatty acids and their metabolites. Polyunsaturated fatty acids were enriched at an early period of lactation, while saturated fatty acids did not change significantly over the period. Moreover, human milk contained high levels of ω-3 fatty acid metabolites, particularly 18-hydroxyeicosapentaenoic acid, an eicosapentaenoic acid-derived metabolite with anti-inflammatory activity. In comparison with human normal milk, thromboxane B2 and protectin D1 levels were significantly elevated in milk from individuals with mastitis, suggesting that these lipid mediators could be potential biomarkers of obstructive mastitis. Overall, the unique lipid profile of human milk supports the efficacy of breast-feeding for supply of more nutritional and bioactive lipids in comparison to artificial or cow milk to infants, in whom digestive and absorptive functions are still immature.

Segregated functions of two cytosolic phospholipase A2 isoforms (cPLA2α and cPLA2ε) in lipid mediator generation.

Among the phospholipase A2 (PLA2) superfamily, group IVA cytosolic PLA2 (cPLA2α) is currently attracting much attention as a central regulator of arachidonic acid (AA) metabolism linked to eicosanoid biosynthesis. Following cell activation, cPLA2α selectively releases AA, a precursor of a variety of eicosanoids, from phospholipids in perinuclear membrane compartments. cPLA2α-null mice display various phenotypes that could be largely explained by reduced eicosanoid signaling. In contrast, group IVE cPLA2ε, another member of the cPLA2 family, acts as a Ca2+-dependent N-acyltransferase rather than a PLA2, thereby regulating the biosynthesis of N-acylethanolamines (NAEs), a unique class of lipid mediators with an anti-inflammatory effect. In response to Ca2+ signaling, cPLA2ε translocates to phosphatidylserine-rich organelle membranes in the endocytic/recycling pathway. In vivo, cPLA2ε is induced in keratinocytes of psoriatic skin, and its genetic deletion exacerbates psoriatic inflammation due to a marked reduction of NAE-related lipids. cPLA2ε also contributes to NAE generation in several if not all mouse tissues. Thus, the two members of the cPLA2 family, cPLA2α and cPLA2ε, catalyze distinct enzymatic reactions to mobilize distinct sets of lipid mediators, thereby differently regulating pathophysiological events in health and disease. Such segregation of the cPLA2α-eicosanoid and cPLA2ε-NAE pathways represents a new paradigm of research on PLA2s and lipid mediators.

Regulatory Roles of Phospholipase A2 Enzymes and Bioactive Lipids in Mast Cell Biology.

Lipids play fundamental roles in life as an essential component of cell membranes, as a major source of energy, as a body surface barrier, and as signaling molecules that transmit intracellular and intercellular signals. Lipid mediators, a group of bioactive lipids that mediates intercellular signals, are produced via specific biosynthetic enzymes and transmit signals via specific receptors. Mast cells, a tissue-resident immune cell population, produce several lipid mediators that contribute to exacerbation or amelioration of allergic responses and also non-allergic inflammation, host defense, cancer and fibrosis by controlling the functions of microenvironmental cells as well as mast cell themselves in paracrine and autocrine fashions. Additionally, several bioactive lipids produced by stromal cells regulate the differentiation, maturation and activation of neighboring mast cells. Many of the bioactive lipids are stored in membrane phospholipids as precursor forms and released spatiotemporally by phospholipase A2 (PLA2) enzymes. Through a series of studies employing gene targeting and lipidomics, several enzymes belonging to the PLA2 superfamily have been demonstrated to participate in mast cell-related diseases by mobilizing unique bioactive lipids in multiple ways. In this review, we provide an overview of our current understanding of the regulatory roles of several PLA2-driven lipid pathways in mast cell biology.

Abnormal male reproduction and embryonic development induced by downregulation of a phospholipid fatty acid-introducing enzyme Lpgat1 in zebrafish.

Phospholipids in the membrane consist of diverse pairs of fatty acids bound to a glycerol backbone. The biological significance of the diversity, however, remains mostly unclear. Part of this diversity is due to lysophospholipid acyltransferases (LPLATs), which introduce a fatty acid into lysophospholipids. The human genome has 14 LPLATs and most of them are highly conserved in vertebrates. Here, we analyzed the function of one of these enzymes, lysophosphatidylglycerol acyltransferase 1 (Lpgat1), in zebrafish. We found that the reproduction of heterozygous (lpgat1+/-) male mutants was abnormal. Crosses between heterozygous males and wild-type females produced many eggs with no obvious cleavage, whereas eggs produced by crosses between heterozygous females and wild-type males cleaved normally. Consistent with this, spermatozoa from heterozygous males had reduced motility and abnormal morphology. We also found that the occurrence of lpgat1 homozygous (lpgat1-/-) mutants was far lower than expected. In addition, downregulation of lpgat1 by morpholino antisense oligonucleotides resulted in severe developmental defects. Lipidomic analysis revealed that selective phospholipid species with stearic acid and docosahexaenoic acid were reduced in homozygous larvae and spermatozoa from heterozygotes. These results suggest that the specific phospholipid molecular species produced by Lpgat1 have an essential role in sperm fertilization and in embryonic development.

Old but New: Group IIA Phospholipase A2 as a Modulator of Gut Microbiota.

Among the phospholipase A2 (PLA2) superfamily, the secreted PLA2 (sPLA2) family contains 11 mammalian isoforms that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using sPLA2-deficient or -overexpressed mouse strains, along with mass spectrometric lipidomics to determine sPLA2-driven lipid pathways, have revealed the diverse pathophysiological roles of sPLA2s in various biological events. In general, individual sPLA2s exert their specific functions within tissue microenvironments, where they are intrinsically expressed through hydrolysis of extracellular phospholipids. Recent studies have uncovered a new aspect of group IIA sPLA2 (sPLA2-IIA), a prototypic sPLA2 with the oldest research history among the mammalian PLA2s, as a modulator of the gut microbiota. In the intestine, Paneth cell-derived sPLA2-IIA acts as an antimicrobial protein to shape the gut microbiota, thereby secondarily affecting inflammation, allergy, and cancer in proximal and distal tissues. Knockout of intestinal sPLA2-IIA in BALB/c mice leads to alterations in skin cancer, psoriasis, and anaphylaxis, while overexpression of sPLA2-IIA in Pla2g2a-null C57BL/6 mice induces systemic inflammation and exacerbates arthritis. These phenotypes are associated with notable changes in gut microbiota and fecal metabolites, are variable in different animal facilities, and are abrogated after antibiotic treatment, co-housing, or fecal transfer. These studies open a new mechanistic action of this old sPLA2 and add the sPLA2 family to the growing list of endogenous factors capable of affecting the microbe-host interaction and thereby systemic homeostasis and diseases.

Group IVE cytosolic phospholipase A2 limits psoriatic inflammation by mobilizing the anti-inflammatory lipid N-acylethanolamine.

Psoriasis is an inflammatory disorder characterized by keratinocyte hyper-proliferation and Th17-type immune responses. However, the roles of bioactive lipids and the regulation of their biosynthesis in this chronic skin disease are not fully understood. Herein, we show that group IVE cytosolic phospholipase A2 (cPLA2 ε/PLA2G4E) plays a counterregulatory role against psoriatic inflammation by producing the anti-inflammatory lipid N-acylethanolamine (NAE). Lipidomics analysis of mouse skin revealed that NAE species and their precursors (N-acyl-phosphatidylethanolamine and glycerophospho-N-acylethanolamine) were robustly increased in parallel with the ongoing process of imiquimod (IMQ)-induced psoriasis, accompanied by a marked upregulation of cPLA2 ε in epidermal keratinocytes. Genetic deletion of cPLA2 ε exacerbated IMQ-induced ear swelling and psoriatic marker expression, with a dramatic reduction of NAE-related lipids in IMQ-treated, and even normal, skin. Stimulation of cultured human keratinocytes with psoriatic cytokines concomitantly increased PLA2G4E expression and NAE production, and supplementation with NAEs significantly attenuated the cytokine-induced upregulation of the psoriatic marker S100A9. Increased expression of cPLA2 ε was also evident in the epidermis of psoriatic patients. These findings reveal for the first time the in vivo role of cPLA2 ε, which is highly induced in the keratinocytes of the psoriatic skin, promotes the biosynthesis of NAE-related lipids, and contributes to limiting psoriatic inflammation.

Group IIA secreted phospholipase A2 controls skin carcinogenesis and psoriasis by shaping the gut microbiota.

Besides promoting inflammation by mobilizing lipid mediators, group IIA secreted phospholipase A2 (sPLA2-IIA) prevents bacterial infection by degrading bacterial membranes. Here, we show that, despite the restricted intestinal expression of sPLA2-IIA in BALB/c mice, its genetic deletion leads to amelioration of cancer and exacerbation of psoriasis in distal skin. Intestinal expression of sPLA2-IIA is reduced after treatment with antibiotics or under germ-free conditions, suggesting its upregulation by gut microbiota. Metagenome, transcriptome, and metabolome analyses have revealed that sPLA2-IIA deficiency alters the gut microbiota, accompanied by notable changes in the intestinal expression of genes related to immunity and metabolism, as well as in the levels of various blood metabolites and fecal bacterial lipids, suggesting that sPLA2-IIA contributes to shaping of the gut microbiota. The skin phenotypes in Pla2g2a-/- mice are lost (a) when they are cohoused with littermate WT mice, resulting in the mixing of the microbiota between the genotypes, or (b) when they are housed in a more stringent pathogen-free facility, where Pla2g2a expression in WT mice is low and the gut microbial compositions in both genotypes are nearly identical. Thus, our results highlight a potentially new aspect of sPLA2-IIA as a modulator of gut microbiota, perturbation of which affects distal skin responses.

Mast Cell-Specific Deletion of Group III Secreted Phospholipase A2 Impairs Mast Cell Maturation and Functions.

Tissue-resident mast cells (MCs) have important roles in IgE-associated and -independent allergic reactions. Although microenvironmental alterations in MC phenotypes affect the susceptibility to allergy, understanding of the regulation of MC maturation is still incomplete. We previously reported that group III secreted phospholipase A2 (sPLA2-III) released from immature MCs is functionally coupled with lipocalin-type prostaglandin D2 (PGD2) synthase in neighboring fibroblasts to supply a microenvironmental pool of PGD2, which in turn acts on the PGD2 receptor DP1 on MCs to promote their proper maturation. In the present study, we reevaluated the role of sPLA2-III in MCs using a newly generated MC-specific Pla2g3-deficient mouse strain. Mice lacking sPLA2-III specifically in MCs, like those lacking the enzyme in all tissues, had immature MCs and displayed reduced local and systemic anaphylactic responses. Furthermore, MC-specific Pla2g3-deficient mice, as well as MC-deficient KitW-sh mice reconstituted with MCs prepared from global Pla2g3-null mice, displayed a significant reduction in irritant contact dermatitis (ICD) and an aggravation of contact hypersensitivity (CHS). The increased CHS response by Pla2g3 deficiency depended at least partly on the reduced expression of hematopoietic PGD2 synthase and thereby reduced production of PGD2 due to immaturity of MCs. Overall, our present study has confirmed that MC-secreted sPLA2-III promotes MC maturation, thereby facilitating acute anaphylactic and ICD reactions and limiting delayed CHS response.

Autophagy Is Required for Maturation of Surfactant-Containing Lamellar Bodies in the Lung and Swim Bladder.

Autophagy is an intracellular degradation system, but its physiological functions in vertebrates are not yet fully understood. Here, we show that autophagy is required for inflation of air-filled organs: zebrafish swim bladder and mouse lung. In wild-type zebrafish swim bladder and mouse lung type II pulmonary epithelial cells, autophagosomes are formed and frequently fuse with lamellar bodies. The lamellar body is a lysosome-related organelle that stores a phospholipid-containing surfactant complex that lines the air-liquid interface and reduces surface tension. We find that autophagy is critical for maturation of the lamellar body. Accordingly, atg-deficient zebrafish fail to maintain their position in the water, and type-II-pneumocyte-specific Fip200-deficient mice show neonatal lethality with respiratory failure. Autophagy suppression does not affect synthesis of the surfactant phospholipid, suggesting that autophagy supplies lipids and membranes to lamellar bodies. These results demonstrate an evolutionarily conserved role of autophagy in lamellar body maturation.

Updating Phospholipase A2 Biology.

The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo.