Journal Article

Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53

Byun, Sanguine, Hakroush, Samy, Mundel, Peter, Sykes, David B., Jo, Seung-Hee, Hiraki, Masatsugu, Yoon, Kyoung Wan, Kwon, Eunjeong, Hwang, So-Young, Weins, Astrid, Cebulla, Angelika, Greka, Anna, Chu, Kiki, Fisher, David E., Lee, Sam W., Mandinova, Anna

2015

Overview

We thought we knew all we needed to about the tumor suppressor p53. However, Yoon et al. now describe a previously unrecognized function of p53 (see the Perspective by Zitvogel and Kroemer). p53 induces expression of the gene encoding DD1α, a receptor-like transmembrane protein of the immunoglobulin superfamily. In conditions of stress, p53 activation can lead to cell death. p53-induced expression of DD1α also promotes the clearance of dead cells by promoting engulfment by macrophages. Furthermore, expression of DD1α on T cells inhibits T cell function. Thus, p53 offers protection from inflammatory disease caused by the accumulation of apoptotic cells, and its suppression of T cells might help cancer cells to escape immune detection. Science , this issue 10.1126/science.1261669 ; see also p. 476 p53 promotes clearance of dead cells and proper immune function. [Also see Perspective by Zitvogel and Kroemer ] 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 Domain1 α ( DD1 α), 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. DD1 α-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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Activation / Amino Acid Sequence / Animals / Apoptosis / Apoptosis - genetics / Apoptosis - immunology / Autoimmune Diseases - genetics / Autoimmune Diseases - immunology / Cancer / Cell Line, Tumor / Clearances / Female / Gene expression / Humans / Immune system / Immunoglobulins / Inflammation - genetics / Inflammation - immunology / Ionizing radiation / Logical Thinking / Macrophages / Macrophages - immunology / Male / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mice, Knockout / Molecular Sequence Data / Mortality / Phagocytosis / Phagocytosis - immunology / Phosphatidylserines - metabolism / Receptors / RESEARCH ARTICLE SUMMARY / Signal Transduction / Suppressors / Tumor Suppressor Protein p53 - metabolism / Tumors