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Gut Microbes 2023utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner....
utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner. However, the impact of T6SS and its secreted effectors on physiological behavior remains poorly understood. In this study, we present Tle1, a phospholipase effector in atypical pathogenic E1 that is secreted by T6SS via its interaction with VgrG1. Tle1 contains a DUF2235 domain and belongs to the Tle1 (type VI lipase effector) family. Bacterial toxicity assays, lipase activity assays and site-directed mutagenesis revealed that Tle1 possessed phospholipase A activity and phospholipase A activity, and that Tle1-induced toxicity required a serine residue (S356) and two aspartic acid residues (D417 and D496). Cells intoxication with Tle1 lead to membrane depolarization and alter membrane permeability. Tli1, a cognate immunity protein, directly interacts with Tle1 to neutralize its toxicity. Moreover, Tle1 can kill multiple microorganisms by T6SS and promote fitness of through mediating antibacterial activity. Tle1 induces bacterial motility by increasing the expression of flagellar-related genes independently of functional T6SS and the tit-for-tat (TFT) response, where uses its T6SS-H1 cluster to counterattack other offensive attackers. Our study also demonstrated that the physical puncture of E1 T6SS can induce a moderate TFT response, which is essential to the Tle1-mediated strong TFT response, maximizing effector functions. Overall, our study characterized the antibacterial mechanism of phospholipase effector Tle1 and its multiple physiological significance.
Topics: Virulence; Phospholipases; Vibrio cholerae; Bacterial Proteins; Gastrointestinal Microbiome; Lipase; Anti-Bacterial Agents; Gene Expression
PubMed: 37526354
DOI: 10.1080/19490976.2023.2241204 -
Frontiers in Cellular and Infection... 2023During bacterial infections, one or more virulence factors are required to support the survival, growth, and colonization of the pathogen within the host, leading to the... (Review)
Review
During bacterial infections, one or more virulence factors are required to support the survival, growth, and colonization of the pathogen within the host, leading to the symptomatic characteristic of the disease. The outcome of bacterial infections is determined by several factors from both host as well as pathogen origin. Proteins and enzymes involved in cellular signaling are important players in determining the outcome of host-pathogen interactions. phospholipase C (PLCs) participate in cellular signaling and regulation by virtue of their ability to hydrolyze membrane phospholipids into di-acyl-glycerol (DAG) and inositol triphosphate (IP3), which further causes the activation of other signaling pathways involved in various processes, including immune response. A total of 13 PLC isoforms are known so far, differing in their structure, regulation, and tissue-specific distribution. Different PLC isoforms have been implicated in various diseases, including cancer and infectious diseases; however, their roles in infectious diseases are not clearly understood. Many studies have suggested the prominent roles of both host and pathogen-derived PLCs during infections. PLCs have also been shown to contribute towards disease pathogenesis and the onset of disease symptoms. In this review, we have discussed the contribution of PLCs as a determinant of the outcome of host-pathogen interaction and pathogenesis during bacterial infections of human importance.
Topics: Humans; Type C Phospholipases; Virulence Factors; Signal Transduction; Inositol Phosphates
PubMed: 37139494
DOI: 10.3389/fcimb.2023.1089374 -
Progress in Lipid Research Jul 2021Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the... (Review)
Review
Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the pancreatic lipase family. PLA1A specifically hydrolyzes sn-1 fatty acid of phosphatidylserine (PS) or 1-acyl-lysophosphatidylserine (1-acyl-lysoPS). PS externalized by activated cells or apoptotic cells or extracellular vesicles is a potential source of substrate for the production of unsaturated lysoPS species by PLA1A. Maturation and functions of many immune cells, such as T cells, dendritic cells, macrophages, and mast cells, can be regulated by PLA1A and lysoPS. Several lysoPS receptors, including GPR34, GPR174 and P2Y10, have been identified. High serum levels and high PLA1A expression are associated with autoimmune disorders such as Graves' disease and systemic lupus erythematosus. Increased expression of PLA1A is associated with metastatic melanomas. PLA1A may contribute to cardiometabolic disorders through mediating cholesterol transportation and producing lysoPS. Furthermore, PLA1A is necessary for hepatitis C virus assembly and can play a role in the antivirus innate immune response. This review summarizes recent findings on PLA1A expression, lysoPS and lysoPS receptors in autoimmune disorders, cancers, cardiometabolic disorders, antivirus immune responses, as well as regulations of immune cells.
Topics: Fatty Acids; Humans; Lysophospholipids; Male; Melanoma; Phosphatidylserines; Phospholipases A1; Skin Neoplasms
PubMed: 34166709
DOI: 10.1016/j.plipres.2021.101112 -
Cell Reports Dec 2023Atg15 (autophagy-related 15) is a vacuolar phospholipase essential for the degradation of cytoplasm-to-vacuole targeting (Cvt) bodies and autophagic bodies, hereinafter...
Atg15 (autophagy-related 15) is a vacuolar phospholipase essential for the degradation of cytoplasm-to-vacuole targeting (Cvt) bodies and autophagic bodies, hereinafter referred to as intravacuolar/intralysosomal autophagic compartments (IACs), but it remains unknown if Atg15 directly disrupts IAC membranes. Here, we show that the recombinant Chaetomium thermophilum Atg15 lipase domain (CtAtg15(73-475)) possesses phospholipase activity. The activity of CtAtg15(73-475) was markedly elevated by limited digestion. We inserted the human rhinovirus 3C protease recognition sequence and found that cleavage between S159 and V160 was important to activate CtAtg15(73-475). Our molecular dynamics simulation suggested that the cleavage facilitated conformational change around the active center of CtAtg15, resulting in an exposed state. We confirmed that CtAtg15 could disintegrate S. cerevisiae IAC in vivo. Further, both mitochondria and IAC of S. cerevisiae were disintegrated by CtAtg15. This study suggests Atg15 plays a role in disrupting any organelle membranes delivered to vacuoles by autophagy.
Topics: Chaetomium; Fungal Proteins; Phospholipases; Recombinant Proteins; Protein Domains; Molecular Dynamics Simulation; Mitochondria; Intracellular Membranes; Saccharomyces cerevisiae; Protein Structure, Tertiary; Models, Molecular; Enzyme Activation
PubMed: 38118441
DOI: 10.1016/j.celrep.2023.113567 -
FASEB Journal : Official Publication of... Jul 2023The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing...
The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A /A and acyltransferase activities. Plaat3-deficient (Plaat3 ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1 mice have not been analyzed. In the present study, we generated Plaat1 mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1 mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1 mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A /A in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.
Topics: Animals; Mice; Diet, High-Fat; Insulin Resistance; Lipid Metabolism; Liver; Phospholipids; Phospholipases; Acyltransferases; Mice, Inbred C57BL
PubMed: 37330992
DOI: 10.1096/fj.202201033R -
Frontiers in Endocrinology 2021The phospholipases A (PLA) superfamily encompasses enzymes commonly found in mammalian tissues and snake venom. Many of these enzymes have unique tissue distribution,... (Review)
Review
The phospholipases A (PLA) superfamily encompasses enzymes commonly found in mammalian tissues and snake venom. Many of these enzymes have unique tissue distribution, function, and substrate specificity suggesting distinct biological roles. In the past, much of the research on secretory PLAs has analyzed their roles in inflammation, anti-bacterial actions, and atherosclerosis. In recent studies utilizing a variety of mouse models, pancreatic islets, and clinical trials, a role for many of these enzymes in the control of metabolism and insulin action has been revealed. In this review, this research, and the unique contributions of the PLA enzymes in insulin resistance and metabolism.
Topics: Animals; Energy Metabolism; Humans; Inflammation; Insulin; Insulin Resistance; Mice; Phospholipases A2, Secretory; Snake Venoms
PubMed: 34512555
DOI: 10.3389/fendo.2021.732726 -
Biochimie Mar 2022Gastrointestinal tract is important for digestion, absorption, detoxification and immunity. Gastrointestinal diseases are mainly caused by the imbalance of protective... (Review)
Review
Gastrointestinal tract is important for digestion, absorption, detoxification and immunity. Gastrointestinal diseases are mainly caused by the imbalance of protective and attacking factors in gastrointestinal mucosa, which can seriously harm human health. Phospholipase A (PLA) is a large family closely involved in lipid metabolism and is found in almost all human cells. A growing number of studies have revealed that its metabolites are deeply implicated in various inflammatory pathways and also regulates the maintenance of numerous biological events such as dietary digestion, membrane remodeling, barrier action, and host immunity. In addition to their phospholipase activity, some members of the superfamily also have other catalytic activities. Based on the in-depth effects of phospholipase A2 on bioactive lipid metabolism and inflammatory cytokines, PLA and its metabolites are likely to be involved in the pathogenesis, development or prevention of gastrointestinal diseases. Therefore, this review will focus on the physiological and pathogenic roles of several important PLA enzymes in the gastrointestinal tract, and reveals the potential of PLA as a therapeutic target for gastrointestinal diseases.
Topics: Gastrointestinal Diseases; Humans; Lipid Metabolism; Phospholipases A2
PubMed: 34974145
DOI: 10.1016/j.biochi.2021.12.014 -
Advances in Neurobiology 2023In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that...
In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.
Topics: Humans; Biological Transport; Brain; Exocytosis; Memory; Phosphatidylinositols; Phospholipases
PubMed: 37615874
DOI: 10.1007/978-3-031-34229-5_14 -
International Journal of Biological... 2022Secreted phospholipases A (sPLAs) participate in a very broad spectrum of biological processes through their enzymatic activity and as ligands for membrane and soluble... (Review)
Review
Secreted phospholipases A (sPLAs) participate in a very broad spectrum of biological processes through their enzymatic activity and as ligands for membrane and soluble receptors. The physiological roles of sPLAs as enzymes have been very well described, while their functions as ligands are still poorly known. Since the last overview of sPLA-binding proteins (sPLA-BPs) 10 years ago, several important discoveries have occurred in this area. New and more sensitive analytical tools have enabled the discovery of additional sPLA-BPs, which are presented and critically discussed here. The structural diversity of sPLA-BPs reveals sPLAs as very promiscuous proteins, and we offer some structural explanations for this nature that makes these proteins evolutionarily highly advantageous. Three areas of physiological engagement of sPLA-BPs have appeared most clearly: cellular transport and signalling, and regulation of the enzymatic activity of sPLAs. Due to the multifunctionality of sPLAs, they appear to be exceptional pharmacological targets. We reveal the potential to exploit interactions of sPLAs with other proteins in medical terms, for the development of original diagnostic and therapeutic procedures. We conclude this survey by suggesting the priority questions that need to be answered.
Topics: Carrier Proteins; Enzyme Activation; Humans; Phospholipases A2, Secretory; Signal Transduction; Structure-Activity Relationship
PubMed: 35002531
DOI: 10.7150/ijbs.68093 -
Free Radical Biology & Medicine Aug 2022Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell... (Review)
Review
Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell death. Oxidized lysophospholipids, formed through the activity of phospholipases and oxidative enzymes and lacking an acyl chain in comparison with parent phospholipids, are now emerging as novel bioactive lipid mediators. Their detection and structural characterization have been limited in the past due to low amounts and the complexity of their biosynthetic and removal pathways, but recent studies have unequivocally demonstrated their formation under inflammatory conditions. The involvement of oxidized lysophospholipids in immune regulation classifies them as damage-associated molecular patterns (DAMPs), which can promote sterile inflammation and contribute to autoimmune and chronic diseases as well as aging-related diseases. Their signaling pathways are just beginning to be revealed. As the first publications indicate that oxidized lysophospholipids use the same receptors as pathogen-associated molecular patterns (PAMPs), it is likely that the inhibition of signaling pathways activated by oxidized lysophospholipids would affect innate immunity per se. On the other hand, inhibition or modulation of their enzymatic formation, which would not interfere with the response to pathogens, might be beneficial and is potentially a promising new field of research.
Topics: Humans; Immunity, Innate; Inflammation; Lysophospholipids; Oxidation-Reduction; Phospholipases
PubMed: 35779690
DOI: 10.1016/j.freeradbiomed.2022.06.228