Throughout the biological world, a 30 Å hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?From the ongoing cataloguing of lipid structures (lipidomics), it is clear that eukaryotic cells invest substantial resources in generating thousands of different lipids 1 . Why do cells use ~5% of their genes to synthesize all of these lipids? The fundamental biological maxim that 'structure subserves function' implies that there must be evolutionary advantages that are dependent on a complex lipid repertoire. Although we now understand the specific functions of numerous lipids, the full definition of the utility of the eukaryotic lipid repertoire remains elusive.Lipids fulfil three general functions. First, because of their relatively reduced state, lipids are used for energy storage, principally as triacylglycerol esters and steryl esters, in lipid droplets. These function primarily as anhydrous reservoirs for the efficient storage of caloric reserves and as caches of fatty acid and sterol components that are needed for membrane biogenesis. Second, the matrix of cellular membranes is formed by polar lipids, which consist of a hydrophobic and a hydrophilic portion. The propensity of the hydrophobic moieties to selfassociate (entropically driven by water), and the tendency of the hydrophilic moieties to interact with aqueous environments and with each other, is the physical basis of the spontaneous formation of membranes. This fundamental principle of amphipathic lipids is a chemical property that enabled the first cells to segregate their internal constituents from the external environment. This same principle is recapitulated within the cell to produce discrete organelles.

Surfactant proteins A and D (SP-A and SP-D) are lung collectins composed of two regions, a globular head domain that binds PAMPs and a collagenous tail domain that initiates phagocytosis. We provide evidence that SP-A and SP-D act in a dual manner, to enhance or suppress inflammatory mediator production depending on binding orientation. SP-A and SP-D bind SIRPalpha through their globular heads to initiate a signaling pathway that blocks proinflammatory mediator production. In contrast, their collagenous tails stimulate proinflammatory mediator production through binding to calreticulin/CD91. Together a model is implied in which SP-A and SP-D help maintain a non/anti-inflammatory lung environment by stimulating SIRPalpha on resident cells through their globular heads. However, interaction of these heads with PAMPs on foreign organisms or damaged cells and presentation of the collagenous tails in an aggregated state to calreticulin/CD91, stimulates phagocytosis and proinflammatory responses.

Mitochondria are dynamic organelles whose functional integrity requires a coordinated supply of proteins and phospholipids. Defined functions of specific phospholipids, like the mitochondrial signature lipid cardiolipin, are emerging in diverse processes, ranging from protein biogenesis and energy production to membrane fusion and apoptosis. The accumulation of phospholipids within mitochondria depends on interorganellar lipid transport between the endoplasmic reticulum (ER) and mitochondria as well as intramitochondrial lipid trafficking. The discovery of proteins that regulate mitochondrial membrane lipid composition and of a multiprotein complex tethering ER to mitochondrial membranes has unveiled novel mechanisms of mitochondrial membrane biogenesis.

Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.antiviral | innate immunity | respiratory epithelium R espiratory syncytial virus (RSV) is an important pathogen that infects 98% of children within the first 2 years of life, and also causes serious disease in elderly individuals and persons with chronic lung disease. In the 1980s, an estimated 100,000 children were hospitalized annually with RSV infection in the United States (1). Although RSV is commonly considered a pediatric disease, it is also highlighted as an opportunistic pathogen (2), with infections producing a mortality rate of 30-100% in immunosuppressed individuals (1). There is growing appreciation that RSV is an important pathogen in elderly and high-risk patients, and a cause of acute exacerbations of asthma (3, 4) and chronic obstructive pulmonary disease (COPD) (5). Over the period 1999-2003, RSV was responsible for hospitalization rates of 10.6% for pneumonia, 11.4% for COPD, 5.4% for congestive heart failure, and 7.2% for asthma (6).No vaccine is currently available for prevention of RSV infection. Several vaccine candidates have not only proved to be ineffective, but have also been shown to lead to vaccine-enhanced disease (7,8). Inhibitors directed against the RSV fusion protein (F protein) were abandoned partly because of the frequency of resistant mutations mapping to the F gene (9). A monoclonal antibody against F protein, Palivizumab, has restricted application and it is recommended for prophylactic use during the RSV season, for high-risk infants (1). Currently the onl...

Phosphatidylserine decarboxylase (PSD1) plays a central role in the biosynthesis of aminophospholipids in both prokaryotes and eukaryotes by catalyzing the synthesis of phosphatidylethanolamine. Recent reports (Trotter, P. J., Pedretti, J., and Voelker, D. R. (1993) J. Biol. Chem. 268, 21416-21424; Clancey, C. J., Chang, S.-C., and Dowhan, W. (1993) J. Biol. Chem. 268, 24580-24590) described the cloning of a yeast structural gene for this enzyme (PSD1) and the creation of the null allele. Based on the phenotype of strains containing a null allele for PSD1 (psd1-delta 1::TRP1) it was hypothesized that yeast have a second phosphatidylserine decarboxylase. The present studies demonstrate the presence of a second enzyme activity (denoted PSD2), which, depending on the method of evaluation, accounts for 4-12% of the total cellular phosphatidylserine decarboxylase activity found in wild type. Recessive mutations resulting in loss of this enzyme activity (denoted psd2) in cells containing the psd1-delta 1::TRP1 null allele also result in ethanolamine auxotrophy. When incubated with [3H]serine these double mutants accumulate label in phosphatidylserine, while very little (< 5%) is converted to phosphatidylethanolamine. In addition, these mutants have a approximately 70% decrease in the amount of total phosphatidylethanolamine even when grown in the presence of exogenous ethanolamine. Strains containing psd1 or psd2 mutations were utilized for the subcellular localization of the PSD2 enzyme activity. Unlike the PSD1 activity, the PSD2 enzyme activity does not localize to the mitochondria, but to a low density subcellular compartment with fractionation properties similar to both vacuoles and Golgi.