1. Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, New York 11743, USA
2. Institute of Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH - 8057 Zurich, Switzerland
3. Institut für Genetik, TU Braunschweig, Spielmannstrasse 7, D - 38106 Braunschweig, Germany
4. Present addresses: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA (J.M.K.); Xybermind GmbH, Lorettoplatz 26, D - 72072 Tübingen, Germany (R.F.); Max Planck Institut für Neurobiologie, Am Klopferspitz 18A, D - 82152 Martinsried, Germany (H.S.)

Correspondence to: Michael O. Hengartner² Correspondence and requests for materials should be addressed to M.O.H. (Email: Michael.Hengartner@molbio.unizh.ch).

Abstract

The removal of apoptotic cells is essential for the physiological well being of the organism^{1, 2, 3}. In Caenorhabditis elegans, two conserved, partially redundant genetic pathways regulate this process^{4, 5, 6}. In the first pathway, the proteins CED-2, CED-5 and CED-12 (mammalian homologues CrkII, Dock180 and ELMO, respectively) function to activate CED-10 (Rac1)^{7, 8}. In the second group, the candidate receptor CED-1 (CD91/LRP/SREC) probably recognizes an unknown ligand on the apoptotic cell⁹ and signals via its cytoplasmic tail to the adaptor protein CED-6 (hCED-6/GULP)^{10, 11}, whereas CED-7 (ABCA1) is thought to play a role in membrane dynamics¹². Molecular understanding of how the second pathway promotes engulfment of the apoptotic cell is lacking. Here, we show that CED-1, CED-6 and CED-7 are required for actin reorganization around the apoptotic cell corpse, and that CED-1 and CED-6 colocalize with each other and with actin around the dead cell. Furthermore, we find that the CED-10(Rac) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the two engulfment pathways and identifying the CED-1, -6 and -7 signalling module as upstream regulators of Rac activation.

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