Abstract
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.
Highlights
An astonishing number of pathogens causing major infectious diseases utilize PS and apoptotic mimicry to evade host immune responses
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]
PS synthesis occurs by two homologous enzymes, phosphatidylserine synthase 1 (PTDSS1) and PTDSS2, both localized in MAMs that appear to have partially redundant activity
Summary
PS externalization during apoptosis and cell stress are mediated by scramblases Xkr[8] 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. 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?
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