Thursday, November 24, 2016 9:46:54 AM
Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.
Facts
PS externalization during apoptosis and cell stress are mediated by scramblases Xkr8 and TMEM16, respectively.
Exposed PS is an evolutionarily conserved anti-inflammatory and immunosuppressive signal.
An astonishing number of pathogens causing major infectious diseases utilize PS and apoptotic mimicry to evade host immune responses.
PS signaling is highly dysregulated in the tumor microenvironment and autoimmune diseases.
PS-targeting therapeutics (e.g., AnxA5, bavituximab) can stimulate immune activity.
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Open Questions
Is PS dysregulation a universal mechanism of immune evasion for bacteria, viruses and protists?
Should PS targeting be considered a global therapeutic option for infectious diseases?
Should PS be considered a global checkpoint inhibitor for cancer?
Are all PS signaling equally immunosuppressive?
Are cofactors involved?
Many critical biochemical pathways require the presence of specific phospholipid classes in the inner and outer leaflet of the plasma membrane. Virtually all eukaryotic cells have an asymmetric distribution of phospholipids across their bilayer membrane, where the choline-containing phospholipids, phosphatidylcholine (PC) and sphingomyelin are predominately maintained on the outer membrane leaflet, and the amino-phospholipids (phosphatidylserine (PS) and phosphatidylethanolamine (PE)) are predominately localized in the inner membrane leaflet.1 This asymmetry is actively maintained by the regulated activity of ATP-dependent lipid transporters. However, membrane asymmetry collapses under a variety of physiological and pathological conditions resulting in dramatic changes in the biochemical properties of the membrane. For example, the redistribution of PS to the external face of the plasma membrane flags cells for their recognition, phagocytosis,2 and ultimate degradation by phagocytes (efferocytosis). Moreover, the interaction between PS-expressing cells and immune cells elicits profound immunological consequences by triggering immunosuppressive pathways that prevent both local and systemic immune activation. Although these pathways are used by apoptotic cells to quell potential immune sequelae against ‘self’, these same pathways are hijacked by pathogens and tumors to promote their sinister life-threatening expansion. Taken together, these observations suggest that PS functions as an upstream immune checkpoint that suppresses the development of immunity. This raises the possibility that PS blockade by the therapeutic administration of PS-targeting agents can restore pathogen and tumor immunity.
PS Asymmetry in Biological Membranes
PS, the most abundant negatively charged glycerophospholipid in eukaryotic membranes, is comprised of a glycerol backbone esterified at the sn-1 and sn-2 carbons of the glycerol moiety with two fatty acyl chains of variable length and saturation, and a phosphate linkage at the sn-3 position (Figure 1).3 Compared with related phospholipids PC and PE, the distinguishing feature of PS is the covalent attachment of serine to the phosphate, giving PS a net negative charge on the head group. Like other glycerophospholipids, PS is synthesized at specialized intracellular structures called mitochondrial-associated membranes (MAMs), structural and functional domains located between the mitochondria and endoplasmic reticulum (ER) that contain enzymes involved in calcium and innate immune signaling, and phospholipid biosynthesis.4 In higher mammals, PS synthesis occurs by two homologous enzymes, phosphatidylserine synthase 1 (PTDSS1) and PTDSS2, both localized in MAMs that appear to have partially redundant activity. Although knockout of either enzyme in mice have unremarkable phenotypes, double PTDSS1/PTDSS2 knockout mice fail to produce PS and is embryonically lethal.5, 6 In contrast, yeast deficient in PTDSS (encoded by a single CHO1 gene) are able to survive when grown on high concentrations of ethanolamine,7 suggesting that PS is an essential membrane lipid in higher metazoans. Interestingly, genetic linkage analysis suggest that rare sporadic dominant gain-of-function mutations in PTDSS1 occur in patients with Lenz-Majewski syndrome, biochemically characterized by increased PS in their membranes, and phenotypically by multiple congenital abnormalities of generalized craniotubular hyperostosis.8
Link:http://www.nature.com/cdd/journal/v23/n6/full/cdd201611a.html
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