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BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module

Nature volume 450, pages 430–434 (2007)Cite this article

Abstract

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms1,2,3. ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses4,5; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment4,5,6. However, the receptor(s) upstream of the ELMO/Dock180/Rac module are still unknown. Here we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region7,8,9 and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key ‘eat-me’ signal exposed on apoptotic cells10,11,12,13, as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac–GEF complex to mediate the uptake of apoptotic cells.

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Figure 1: Identification of BAI1 as an ELMO1-interacting protein.
Figure 2: BAI1 enhances uptake of apoptotic targets.
Figure 3: Recognition of phosphatidylserine by TSRs.
Figure 4: BAI1 functions upstream of the ELMO/Dock180/Rac module.

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Acknowledgements

We thank J. Casanova, C. Grimsley and members of the Ravichandran laboratory for suggestions and for critical reading of the manuscript. This work was supported by grants from the National Institute of General Medical Sciences (to K.S.R.). M.R.E. was supported by a postdoctoral fellowship from the American Cancer Society, and Z.M. was supported by a postdoctoral fellowship through the BioDefense Training grant (NIH).

Author Contributions D.P. performed and analysed most of the experiments in this study. A.C.T. performed Amnis Imagestream studies and the confocal microscopy analyses. M.R.E. helped with RT–PCR analyses and the in vivo mouse studies with BAI1-TSR. M.L. generated ELMO1 knockdown 774 cells. L.B.H. analysed the GEF activity associated with BAI1 and provided technical help in other parts of the manuscript. Z.M. performed the lipid membrane strip binding assay of the TSR protein. A.L.K. generated 2-μm lipid vesicles. J.W.S. provided primary astrocytes, technical expertise and critical intellectual input with these studies. K.S.R. provided overall coordination with respect to conception, design and supervision of the study. K.S.R. also wrote the manuscript with comments from co-authors.

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  1. Mingjian Lu

    Present address: Present address: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.,

Authors and Affiliations

  1. Department of Cell Biology,,

    Daeho Park

  2. Carter Immunology Center,,

    Daeho Park, Annie-Carole Tosello-Trampont, Michael R. Elliott, Lisa B. Haney, Zhong Ma & Kodi S. Ravichandran

  3. Department of Microbiology,,

    Mingjian Lu & Kodi S. Ravichandran

  4. Cardiovascular Division and,,

    Alexander L. Klibanov

  5. Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA,

    James W. Mandell

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  1. Daeho Park
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Correspondence to Kodi S. Ravichandran.

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Park, D., Tosello-Trampont, AC., Elliott, M. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007). https://doi.org/10.1038/nature06329

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