Phospholipids: Dynamic Lipid Signaling in Health and Diseases

Dear Colleagues,

It is now amply recognised that phospholipid signalling is one of the most important signal transduction pathways used by cell-surface receptors to control intracellular events, and functions as a key homeostatic regulator, orchestrating cell activities.

Phospholipid signalling is able to actively influence their resident cells’ physiology, integrating complex signals in space and time, and plays key roles in development and tissue homeostasis by controlling a variety of cellular processes, such us proliferation, differentiation, adhesion and movement, metabolism, pluripotency, stemness, and death. The wide range of biological processes in which the specific involvement of phospholipid signalling is involved explains the need for phospholipid structural diversity. Indeed, phospholipids, with their glycero- and sphingo-phospholipid classes, constitute a large superfamily of membrane lipids, exhibiting an extraordinary structural heterogeneity, mainly derived from their diversity in the hydrophobic acyl/sphingoid tails, which adds a high level of complexity to that conferred by the polar head group.

Many advances have been made over the last decade in signal sensing centred on phospholipids. Many research studies have revealed that phospholipids maintain homeostasis through a complex and dynamic network of metabolic events, regulated by multiple enzymes, whose activities are highly responsive to extracellular and intracellular factors. This multitude of phospholipid metabolic pathways is responsible for the formation of a large and structurally complex group of signalling molecules. The number of effectors that exist, even within a single cell, creates an extremely complex signalling web downstream of phospholipid signalling activation. Recent studies revealed important aspects of phospholipid signalling, and the relevance of their spatiotemporally diverse and dynamic molecular profile, including their multiple locations in either specific membrane microdomains, or distinct intramembrane pools, or different subcellular sites and compartments, as well as different extracellular fluids. Along with their metabolic products, phospholipids play a crucial role in signalling events implicated in a wide range of biological processes, regulating survival, growth, differentiation, shape, motility, activation, and death. An intriguing aspect of phospholipid signalling recently emerged from the evidence that several phospholipids and their derivatives play a critical role as transcriptional regulators of complex nuclear signalling pathways. Indeed, some phospholipid species can act as non-membrane associated lipids to specifically bind and functionally regulate the activity of certain nuclear receptors. Moreover, some nuclear receptors can bind a phospholipid head group to key phospholipid signalling enzymes, which can then modify the phospholipid head group with unique kinetic properties. Thus, phospholipid signalling represents a complex, highly controlled network of metabolic pathways that is essential for effective cellular responses, intercellular communication, and the regulation of homeostasis.

A further strength of phospholipid signalling resides in the generation of lysophospholipids, small lipid signals that can be secreted by some cell types to act as extracellular autocrine/paracrine signals through binding to specific receptors. The relevance of this extracellular signalling is underscored by multiple evidence demonstrating the roles of lysophospholipids in the regulation of different key processes ranging from embryo development to neurogenesis, vasculogenesis and immune response, as well as their implication in multiple human diseases.

Recent studies also revealed an additional complexity to the multifaceted mechanisms of phospholipid signalling, that is its involvement in the regulation of extracellular vesicles. These small, secreted vesicular structures are emerging as a new frontier of signal transduction, involved in intercellular communication, and the maintenance of physiological homeostasis. These vesicles appear to transport specific phospholipid enzymes/signals to provide a mean of their efficient delivering at great distances, without dilution or degradation, to different cells.

Given the key role and the wide array of cell regulatory functions of phospholipid signalling, its dysregulation is, as expected, the cause of many diseases. Evidence has recently accumulated showing that defects in phospholipid signalling occur in, and contribute to, driving the onset of a range of human diseases. Numerous findings indicate that alterations of phospholipid signalling can promote the progression of several disorders, being involved in developmental and degenerative diseases, and having an intricate role in complex diseases such as cancer, cardiovascular and neurodegenerative disorders. A relevant, active area of research focuses on the understanding of the factors that induce the signalling switch to a pathological role, and on the development of novel therapeutic modalities

This Special Issue seeks reviews and original papers covering a wide range of topics related to phospholipid signalling, with the aim of providing recent advances, new concepts and new ideas on the mechanisms underlying phospholipid signalling in health and disease. The objective is to highlight the current state of the art regarding phospholipid signalling, its biological relevance in physiological contexts, and to provide us with an understanding of its impact on human diseases, and how it can be modulated in disease to gain a therapeutic benefit. The field needs input from biophysicists, biochemists, molecular and cell biologists, physiologists, pathologists, and clinicians.

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• phospholipid signalling
• lysophospholipids
• phospholipases
• lipid kinases
• lipid phosphatases

• Phospholipids: Dynamic Lipid Signaling in Health and Diseases - Series 2 in Cells (4 articles)