Bai1 is an engulfment receptor for apoptotic cells upstream of the elmo/dock180/rac module

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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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. AUTHOR INFORMATION Author notes * 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 * Department of Cell Biology,, Daeho Park *

Carter Immunology Center,, Daeho Park, Annie-Carole Tosello-Trampont, Michael R. Elliott, Lisa B. Haney, Zhong Ma & Kodi S. Ravichandran * Department of Microbiology,, Mingjian Lu & 

Kodi S. Ravichandran * Cardiovascular Division and,, Alexander L. Klibanov * Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA, James W. Mandell Authors *

Daeho Park View author publications You can also search for this author inPubMed Google Scholar * Annie-Carole Tosello-Trampont View author publications You can also search for this author

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for this author inPubMed Google Scholar * Lisa B. Haney View author publications You can also search for this author inPubMed Google Scholar * Zhong Ma View author publications You can also

search for this author inPubMed Google Scholar * Alexander L. Klibanov View author publications You can also search for this author inPubMed Google Scholar * James W. Mandell View author

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CORRESPONDING AUTHOR Correspondence to Kodi S. Ravichandran. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION The file contains Supplementary Figures S1-S9 with Legends. (PDF 1145 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 26 July 2007 * Accepted: 01 October 2007 * Published: 15 November 2007 * Issue Date: 15 November 2007 * DOI:

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