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Functional Diversity in a Lipidome COMMENTARY COMMENTARY Functional diversity in a lipidome COMMENTARY Padinjat Raghua,1 Lipids are complex molecules generated by cells species is distinct in these situations (4). These obser- through enzymatic mechanisms from simpler constit- vations have raised a number of intriguing questions: uents. Each complex lipid typically consists of a head 1) Do these individual species have distinct biochem- group with a unique chemical composition that is es- ical functions in cells? 2) What is the molecular mech- terified to hydrophobic tails composed of fatty acyl anism through which individual molecular species of a chains or sphingoid bases. Based on their composi- given lipid influence cellular function? 3) What deter- tion, lipids are classified into eight major categories mines the range of molecular species for a given lipid (fatty acyls, glycerolipids, glycerophospholipids, sphin- class? In PNAS, Schuhmacher et al. (5) address some golipids, sterols, prenols, glycolipids or saccharolipids, of these questions in the context of diacylglycerol and polyketides), each of which is subdivided into clas- (DAG), a class of glycerolipid with well-established ses and subclasses (1). The biological functions of a lipid functions in cells. class are widely regarded as defined by the lipid head Like most other lipid classes, cells contain many group. For example, phosphatidylinositols are a lipid molecular species of DAG that differ from each other class defined by the presence of an inositol head group, with respect to the composition of the fatty acyl chains and their cellular function as signaling molecules is crit- in the tail of the lipid. DAGs are produced by multiple ically dependent on the inositol head group and mod- enzymatic pathways; they are a key intermediate in ifications thereof. However, for each lipid class, there phospholipid biosynthesis but are also a well-studied are also a number of unique molecular species, all of signaling intermediate in eukaryotic cells. Many cells which have identical head groups but vary with respect activate phospholipase C (PLC) as a mechanism of to the number of carbon atoms in the acyl chains, the signaling. PLC generates DAG and inositol 1,4, 5 number of double bonds, and also the nature of the trisphosphate (IP3) by the hydrolysis of the signaling chemical linkage (ester or ether) of these chains to the lipid phosphatidylinositol 4,5-bisphosphate (PIP2). 2+ head group. For example, in mammalian tissues or Whereas IP3 releases Ca from intracellular stores cells, 30 to 35 species of a specific lipid class can be (6), DAG activates protein kinase C (PKC), leading to detected and quantified (2), and with the advent of further biochemical changes and cellular effects (7). highly sensitive mass spectrometry, the bewildering Like other lipid classes, phosphatidylinositol, the pre- complexity of lipid species within a single class has be- cursor of PIP2, is also found as multiple molecular spe- come apparent. Taken together across all lipid classes, cies, and therefore this is also the case with PIP2. When mammalian cells may have thousands of individual mo- mammalian cells are stimulated with agonists for G- lecular species of lipids; these have collectively been protein–coupled receptors, multiple species of DAGs referred to as the lipidome (3). are produced with specific temporal kinetics. These The presence of such a lipidome is a feature of all include DAG species that are highly unsaturated as cell types and common model organisms examined to well as monounsaturated DAG species (reviewed in date, including mammals, Drosophila melanogaster, ref. 8). Previous studies have attempted to test the Caenorhabditis elegans, and yeast, and thus appears efficacy of these DAG species to activate PKC (9) to be conserved in evolution. However, the repertoire and found that, in vitro, polyunsaturated DAGs are of lipid molecular species varies between organisms. far more effective that monounsaturated species. A range of molecular species is also seen for a given However, the relevance of this finding to signaling lipid class both in primary cells (i.e., directly isolated activity within intact cells has remained unclear. from an organism) as well as cells maintained contin- In their study, Schuhmacher et al. (5) use the tools uously in culture, although the repertoire of molecular of chemical biology to synthesize individual molecular aNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India Author contributions: P.R. wrote the paper. The author declares no competing interest. Published under the PNAS license. See companion article, “Live-cell lipid biochemistry reveals a role of diacylglycerol side-chain composition for cellular lipid dynamics and protein affinities,” 10.1073/pnas.1912684117. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.2004764117 PNAS Latest Articles | 1of3 Downloaded by guest on September 23, 2021 Fig. 1. Chemical structure of two individual molecular species of DAG: (A)18:0j 20:4 DAG (1-stearoyl-2-arachidonoyl-sn-glycerol) and (B)8:0j 8:0 DAG (1,2-dioctanoyl-sn-glycerol). The acyl chain 18:0 is in green, 20:4 is in red, and 8:0 is in pink. The common head group (i.e., the glycerol moiety) is shown in blue. species of DAG including stearyl arachidonyl DAG (SAG) as well lipid bilayer, are able to influence the ability of its head group to as dioctanoyl DAG (DOG) (Fig. 1). SAG is the primary species of interact with protein ligands recruited to the membrane. The mo- DAG produced after PLC activation in mammalian cells. The lecular mechanism underlying this recognition of acyl chain length DAG species were also functionalized with additional chemical and unsaturation by protein ligands remains to be understood. groups to allow them to be loaded onto intact cells, their spatial Furthermore, this observation has implications for the common distribution visualized using fluorescence microscopy, and a UV- approach of using the interaction of a lipid head group with its sensitive chemical cage allowed them to be released and made fluorescently tagged binding domain as a reporter of lipid local- available to activate PKC at the plasma membrane with temporal ization in intact cells. Indeed, Schuhmacher et al. (5) report that precision. During cell signaling, the production of DAG at the the ability of specific molecular species of DAG to recruit full- plasma membrane leads to the recruitment of PKC through the length PKC is not well correlated with their ability to recruit the interaction of its C1 domain with this lipid, a key event in PKC isolated C1 domain of PKC (10). A second practical implication activation. To observe PKC recruitment in intact cells, the au- of these findings arises from the use of short-chain lipids to test thors used a version of PKC tagged to green fluorescent protein the ability of a specific lipid class to stimulate protein activity in and monitored its translocation to the plasma membrane. This cell physiology experiments. Typically, short acyl chain analogs combination of experimental features allows a precise assess- of lipids (such as DOG) are used in preference to the longer ment of the ability of individual species of DAG on the activation chain, unsaturated species (such as SAG) that have poor solubil- of PKC in space and time. ity and are difficult to handle in aqueous buffers used for cell Schuhmacher et al. (5) find that individual molecular species of physiology experiments. The interpretation of the results of such DAG, when generated at the plasma membrane through photol- experiments will need to be reconsidered, especially in scenar- ysis of caged precursor probes, differ in their ability to recruit PKC ios in which cell physiology is not modulated by the addition to the plasma membrane. While SAG was most effective in PKC of DOG. recruitment to the plasma membrane, DOG was the least effec- The findings of Schuhmacher et al. (5) raise questions on tive. The individual isoforms of PKC (i.e., PKC α, β, γ, δ, and e) also whether the selective activation of PKC by SAG is an exceptional differed in their ability to translocate to the plasma membrane in finding. This may not be the case, because previous studies have response to uncaging of individual species of DAG. The ability of reported additional enzymes in the PLC-triggered cycle of lipid individual DAG species to recruit PKC to the plasma membrane metabolism that also show a preference for SAG. These include was well correlated with their ability to modulate downstream diacylglycerol kinase e, which appears to prefer SAG as a sub- outputs of PKC signaling (such as c-Raf and GSK3β) under equiv- strate; phosphatidylinositol 4-phosphate 5-kinase, which appears alent conditions. Together, these findings offer compelling evi- to prefer 1-stearyl 2-arachidonyl PI4P (reviewed in ref. 11); and dence that, in intact cells, individual molecular species of DAG CDS2, which shows strong selectivity for 1-stearoyl-2-arachido- differ in their ability to relay information during cell signaling. noyl-sn-phosphatidic acid as substrate (12). Although these are These findings have a number of important implications. First, all enzymes and therefore expected to have substrate specificity, they imply that the biochemical activity of a lipid class is not it is important to note that the specificity in question is at the level merely a function of the head group that defines that class. of the acyl chain composition of the respective substrate. Simi- Clearly, as Schuhmacher et al. (5) find, the hydrophobic tail of a larly, the binding of specific classes of lipids by lipid transfer pro- lipid, acyl chains in the case of DAG, although embedded in the teins also appears to show acyl chain specificity (13, 14). Thus, it 2of3 | www.pnas.org/cgi/doi/10.1073/pnas.2004764117 Raghu Downloaded by guest on September 23, 2021 might be that some of the numerous molecular species of any Schuhmacher et al.
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