Phospholipid recognition: Saying BAI-BAI to apoptotic cells
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Phosphatidylserine, which decorates apoptotic cells and triggers macrophage engulfment, is a novel ligand for the BAI1 and Tim4 transmembrane receptors and promotes corpse uptake by activating Rac.
The phospholipid phosphatidylserine (PS) dots the surface of apoptotic cells and therefore distinguishes live cells from cell corpses. Recognition of PS promotes a series of cytoskeletal rearrangements in macrophages that enables them to engulf and destroy apoptotic cell corpses. The Rac small GTPase and the ELMO/Dock180 guanine nucleotide exchange factor (GEF) complex are critical engulfment mediators; however, the biological link between PS expression and Rac activation has remained elusive. In Nature, Park et al. now show that PS is a ligand for the seven-transmembrane receptor BAI1 (brain-specific angiogenesis inhibitor 1), which activates Rac and promotes apoptotic cell engulfment.
An interaction between ELMO and BAI1 was observed in a yeast two-hybrid screen and confirmed by co-immunoprecipitation experiments with endogenous proteins. Exogenous expression of BAI1 in macrophages promoted the binding and engulfment of cell corpses, implicating BAI1 in both apoptotic cell recognition and uptake. Conversely, mutations blocking the BAI1/ELMO interaction abolished BAI1-mediated engulfment.
BAI1 contains five thrombospondin repeats (TSRs) in its extracellular domain. TSRs are known to bind to PS, and indeed the TSR region of BAI1 specifically bound PS in vitro. Furthermore, BAI1-mediated recognition of PS was important for corpse uptake, as cells that expressed BAI1 selectively engulfed a synthetic substrate containing PS. Removal of the extracellular domain of BAI1 blocked PS-stimulated uptake, indicating that PS is a novel ligand for BAI1 that promotes its engulfment activity.
Next, the authors evaluated the role of the Dock180/ELMO/Rac complex in mediating engulfment upon BAI1 activation. PS stimulation of BAI1 promoted rapid and transient Rac activation. The interaction between Dock180, ELMO and Rac has been well characterized, and the authors confirmed the importance of all three components in BAI1-mediated macrophage activation. Expression of a Dock180 mutant unable to activate Rac, or expression of an ELMO mutant capable of binding BAI1 but not Dock180 abolished engulfment. The importance of PS in stimulating this cascade was confirmed in vivo through competitive inhibition of the BAI1/PS interaction.
Similar to BAI1, Miyanishi et al. report in Nature that the Tim1 and Tim4 (T-cell immunoglobulin- and mucin-domain-containing molecule) transmembrane receptors can directly engage PS exposed on apoptotic cells. Overexpression of Tim1/4 promoted corpse uptake, although the signaling pathway that Tim1/4 stimulates to mediate engulfment is not yet known. These two studies describe PS as a novel ligand for transmembrane receptors and elucidate the mechanism by which PS expression on apoptotic cells leads to engulfment. It remains to be determined whether the Tim proteins and BAI1 have overlapping or non-redundant roles in promoting apoptosis.
Emily J. Chenette Signaling Gateway
Reference
Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature450, 430-434 (2007) | Article | PubMed |
Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura , T. & Nagata, S. Identification of Tim4 as a phosphatidylserine receptor. Nature450, 435-439 (2007) | Article | PubMed |
