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Phosphatidylserine Hide-And-Seek COMMENTARY COMMENTARY Phosphatidylserine hide-and-seek COMMENTARY Suzanne Corya,b,1 Every day, billions of new cells are produced in our sites within a cytoplasmic loop; once apoptosis is acti- bodies, and an equivalent number must die. Normally vated, cleavage of these sites irreversibly inactivates this occurs by apoptosis (1), during which the chroma- their flippase function (Fig. 1B). However, while it is tin compacts against the nuclear envelope, followed an obligatory step, loss of flippase activity is not suffi- rapidly by nuclear fragmentation and budding into cient to rapidly expose PtdSer due, in part, to the un- multiple membrane-bound apoptotic bodies. This favorable kinetics of a phospholipid with a polar head “dance of death” results from the activation of certain group moving through the hydrophobic lipid layer. Thus, proteases known as caspases, culminating in activa- efferocytosis cannot proceed unless the target cells tion of effector caspases-3 and -7, which target hun- also activate a scramblase, which can translocate phos- dreds of vital cellular proteins. Importantly, because pholipids bidirectionally between the inner and outer there is no cell membrane rupture, apoptotic cell leaflet of the plasma membrane. death provokes no inflammatory response, in contrast Using heroic expression cloning, Nagata and co- to cell death by necrosis, necroptosis, or pyroptosis. workers (6, 7) previously identified two such scram- However, in our bodies, as in our communities, proper blases, XKR8 and TMEM16F, each of which is ubiq- disposal of detritus is vital for our health. Thus, the ap- uitously expressed and belongs to an extended protein optotic corpses are recognized and rapidly removed by family. XKR8, which has 10 predicted transmembrane phagocytic cells, a process termed efferocytosis. Much domains and cytoplasmic N and C termini, is trans- of what we currently understand about efferocytosis has ported to the plasma membrane complexed 1:1 with a been established by research conducted in Shigekazu chaperone protein: basigin or neuroplastin. Caspase-3– ’ Nagata s laboratory, including the PNAS paper by mediated cleavage near the C terminus of XKR8 trig- Segawa et al. (2), which describes how efferocytosis gers formation of an active homodimeric heterodimer can be turned upon live B cell progenitors, provoking with scramblase activity (7). In apoptotic cells, PtdSer severe B cell lymphopenia. exposure by XKR8 is irreversible due to the con- comitant inactivation of ATP11 flippases by caspase-3 “ ” Hanging Out the Eat Me Signal (7, 8) (Fig. 1B). TMEM16F, in contrast, mediates tran- + Disposal of apoptotic bodies by phagocytes man- sient PtdSer display by healthy cells undergoing Ca2 - + dates that they are clearly distinguishable from normal mediated activation or exposed to Ca2 ionophores + cells. The critical (eat me) signal is the presence of (6, 9) (Fig. 1C). Ca2 binds to and stabilizes TMEM16F phosphatidylserine (PtdSer) in the outer leaflet of the as a homodimer, which then translocates PtdSer from – plasma membrane (3 5). In healthy cells, nearly all the inner to the outer leaflet of the plasma membrane PtdSer molecules (and other aminophospholids) are via charged residues in its transmembrane segments confined to the inner leaflet of the plasma membrane (10, 11). due to the activity of ATP-dependent phospholipid flippases, including the P4-type ATPases ATP11A and Engulfment by “Tethering and Tickling” ATP11C. Together with their chaperone, CDC50A, How does PtdSer exposure on cells undergoing apo- these proteins specifically translocate PtdSer from ptosis trigger their engulfment by macrophages? To the outer to the inner leaflet of the plasma membrane answer this question, Nagata and coworkers searched (Fig. 1A). for PtdSer-binding receptors expressed by macro- How, then, does PtdSer become externalized in phages. Surprisingly, they found two very different cells undergoing apoptosis? The answer is that both types of molecules: TIM4, a macrophage transmembrane ATP11A and ATP11C have several caspase-3 recognition protein (12), and MFG-E8, originally discovered as a aMolecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and bDepartment of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia Author contributions: S.C. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion article 10.1073/pnas.1814323115. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1817485115 PNAS Latest Articles | 1of3 Downloaded by guest on September 30, 2021 A B C D Fig. 1. Phospholipid redistribution dynamics at the plasma membrane. (A) In normal cells, flippases ATP11A and ATP11C, heterodimerized with their chaperone, CDC50A, continuously translocate PtdSer from the outer to the inner leaflet of the plasma membrane (unidirectional gray arrow), and the scramblases XKR8 and TMEM16F are inactive. (B) In cells undergoing apoptosis, caspase-3 cleavage irreversibly inactivates ATP11A/11C. In addition, caspase-3 cleaves XKR8, and the truncated XKR8, together with either basigin (BSG) or neuroplastin (NPTN), undergoes dimerization and + + bidirectionally translocates phospholipids (bidirectional gray arrow). (C) In cells undergoing Ca2 -mediated activation, TMEM16F is stabilized by Ca2 binding, dimerizes, and scrambles phospholipids (bidirectional gray arrow), and the flippases are probably transiently inactivated. (D)Engulfmentby phagocytic cells of apoptotic cell bodies or live cells exposing PtdSer. A, N, and P refer to the actuator, nucleotide-binding, and phosphorylation domains of the cytoplasmic region of ATP11A/C. (Further details are provided in the main text and in ref. 16.) Adapted with permission from Annual Reviews, from ref. 16 and from ref. 22, with permission from Elsevier. Permission conveyed through Copyright Clearance Center, Inc. major component of milk fat globules (13). Two other soluble Engulfment Can Be Cannibalistic PtdSer-binding proteins, protein S (ProS) and growth arrest-specific Segawa et al. (2) reveal that engulfment can become cannibalistic. 6 (Gas6), have also been identified (14, 15). TIM4 binds PtdSer via The gene encoding the ATP11C flippase is located on the X −/+ an extracellular IgG domain, thereby directly coupling the dying chromosome in mice; hence, male ATP11C mice (hereafter ATP11C−/y cell to the engulfing cell. In contrast, the soluble PtdSer-binding ) are null for ATP11C. Unexpectedly, two research proteins serve as bivalent hooks to link the phagocyte to its prey. groups independently discovered such mice while screening MFG-E8, which is secreted from certain types of macrophages and mutagenized mice for blood cell abnormalities (17, 18). Male mice in these strains exhibited a severe deficit of circulating B cells. immature dendritic cells, binds the macrophage αvβ3/5-integrin Segawa et al. illuminate the cause of their B lymphopenic phe- complex, whereas ProS and Gas6 bind to a macrophage Tyro3– notype: engulfment by bone marrow macrophages of live B cell Axl–MerTK (TAM) tyrosine kinase receptor (Fig. 1D). Engulfment progenitors unable to reverse transient PtdSer exposure. requires tethering and tickling (16). First, the PtdSer-exposing cel- − y While B cell development in ATP11C / mice is blocked at the lular buds are trapped by TIM4. Once tethered, they become ad- pro-B cell stage, T cell development, surprisingly, is normal (17, 18). ditionally bound by MFG-E8/integrin and/or ProS(Gas6)/TAM and Predicting that this difference between T and B lymphopoiesis the tickling starts: tyrosine phosphorylation, activation of Rac1, ac- reflected differential expression of ATP11A and ATP11C, Segawa tin polymerization, formation of the phagocytic cup, and, finally, et al. (2) undertook qPCR analysis and found that all thymic T cell transportation of the engulfed cell body to lysosomes within the subpopulations in WT mice expressed both ATP11A and ATP11C phagocytes for demolition and reuse of amino acids and other mRNAs, but the B lymphoid subpopulations in the bone mar- cell constituents. row expressed only ATP11C. Thus, whereas T cells developing in 2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1817485115 Cory Downloaded by guest on September 30, 2021 − y ATP11C / mice remain flippase competent because they still ex- Remaining Enigmas press ATP11A, their B lymphoid counterparts are flippase incom- In addition to solving an intriguing puzzle, Segawa et al.’s (2) study petent because they fail to express either ATP11A or ATP11C. of ATP11C-deficient mice raises many interesting issues for future Having previously found that W3 T lymphoma cells lacking investigation. First, is the suppression of ATP11A expression in flippase activity due to CDC50A deficiency can be engulfed alive early B cell development merely an accidental by-product of in a PtdSer-dependent manner (5), Segawa et al. postulated that developmental epigenetics or does it provide some physiological ATP11C −/y the B lymphopenic phenotype of mice was due to benefit? Second, why do developing B cell progenitors expose engulfment of live B cell progenitors by bone marrow macro- PtdSer? The small population of nonapoptotic but PtdSer-positive phages. If so, they reasoned that inhibiting the TAM receptors in B cell progenitors found in WT mice (19, 20) and amplified in macrophages should reverse the B lymphopenia. ATP11C-null mice (2) has apparently undergone activation of a To test this hypothesis, they
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