Control of Signaling-Mediated Clearance of Apoptotic Cells by the Tumor Suppressor p53

Science. 2015 Jul 31;349(6247):1261669. doi: 10.1126/science.1261669.

Abstract

The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Cell Line, Tumor
  • Female
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Macrophages / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Phagocytosis / immunology*
  • Phosphatidylserines / metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Dies1 protein, mouse
  • GI24 protein, human
  • Membrane Proteins
  • Phosphatidylserines
  • Tumor Suppressor Protein p53