Review
Shaping up the membrane: diacylglycerol coordinates spatial orientation of signaling

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Diacylglycerol signals by binding and activating C1 domain-containing proteins expressed principally in neuronal and immune tissues. This restricted expression profile suggests that diacylglycerol-regulated signals are particularly relevant in cell–cell communication processes in which active endocytosis and exocytosis take place. Not surprisingly, various experimental approaches have demonstrated a crucial role for diacylglycerol effectors and metabolizing enzymes in the control of immune responses, neuron communication and phagocytosis. Current research delineates a scenario in which coordinated decoding of diacylglycerol signals is translated into complex biological responses such as neuronal plasticity, T cell development or cytolytic killing. Diacylglycerol functions reach maximal diversity in these highly specialized systems in which signal intensity directly regulates distinct biological outcomes. This review brings together the most recent studies, emphasizing the contribution of compartmentalized DAG metabolism to orientated signaling events.

Section snippets

Half a century of diacylglycerol research

Since the initial characterization, over four decades ago, of receptor-dependent inositol phospholipid hydrolysis, the generation of a diacylglycerol (DAG) pool with signaling properties has been one of the best-studied models of receptor-regulated signaling. The identification of the protein kinase C (PKC) family as DAG-regulated kinases, and later as receptors for the tumor-promoting DAG analog phorbol ester (PE), intensified the search for DAG-based mechanisms. Studies over the years

The where and when of DAG: C1 domains as bioprobes

Decoding DAG signals in the cell requires the structurally conserved protein kinase C type I (C1) domains, whose α-helix and two antiparallel β-sheets form two flexible loops that generate a binding pocket into which the lipid is inserted. Originally described as a conserved region responsible for allosteric activation of PKC isozymes, C1 domains are found in other DAG effector proteins, including PKD, chimaerins, Unc13 and RasGRP. Non-DAG-binding ‘atypical’ C1 domains are found in some

The immune synapse: a polarized site of DAG action

IS formation between T cells and APCs is a clear example of DAG function in signaling, polarization and trafficking. Large morphological changes are produced in T cells during synapse formation. After specific antigen recognition, the T cell receptor (TCR) is activated and organizes a structured signaling platform, with extensive membrane remodeling and organelle reorganization; the secretory machinery, Golgi apparatus, microtubule-organizing center (MTOC) and mitochondria then polarize towards

DAG function in the neuronal synapse: both sides of the story

Neurons are highly structured cells, divided morphologically into a presynaptic area at the axon terminals and a postsynaptic area with dendrite spines; in a secretory synapse, the former specialize in neurotransmitter secretion, whereas the latter is enriched in receptors and signal transduction proteins [18] (Figure 3b). Communication between these areas establishes continuous structural modifications, weakening or strengthening contacts and allowing synapse plasticity. This is especially

Phagocytosis: linking membrane remodeling to effector signals

During phagocytosis, cells of the innate immune system (macrophages and neutrophils) engulf invading pathogens and apoptotic bodies. Promoted by various receptors (Fc, complement, mannose and lipopolysaccharide (LPS) receptors, as well as integrins), phagocytic cells create an extended pseudopod to provide a membrane area where the nascent phagosome will be generated [47]. Lipids participate in both processes by governing membrane remodeling and triggering signaling pathways important for

C1 domains: playing hide-and-seek

Although C1 motifs share considerable similarity between DAG-responding proteins, alterations in their sequences confer differences in affinity, penetration and membrane specificity, which regulate their activation mechanisms 3, 59. DAG responses are controlled at several levels. At the secondary structural level, groove accessibility might be sterically impeded in the C1 motif, necessitating greater conformational change for DAG insertion; this is the case of the Munc13 C1 domain, in which a

Concluding remarks

Our knowledge of diacylglycerol metabolism and function has expanded greatly since its initial characterization as the PKC allosteric modulator. The original concept of DAG as a transient recruiter of protein kinases to the plasma membrane has evolved to a complex picture in which DAG generation and consumption delimits ‘hot’ areas in the cell where secretion, receptor endocytosis, cytoskeletal reorganization and protein phosphorylation act in coordination.

The large scaffolds where

Acknowledgments

We sincerely apologize to all those authors whose work cannot be cited here owing to space limitations. We thank Drs Severine Gharbi, Mar Valés, Hugh Reyburn and Manuel Izquierdo for critical reading and comment, and Catherine Mark for excellent editorial assistance. M.A. is a recipient of a fellowship from the Madrid Regional Government. Work in the author's laboratory is supported by grants from the Spanish Ministry of Health (Instituto de Salud Carlos III; RD067002071035), the Spanish

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