Cell polarity and adherens junction formation inhibit epithelial Fas cell death receptor signaling.

J Cell Biol. 2018 Sep 21. pii: jcb.201805071. doi: 10.1083/jcb.201805071. [Epub ahead of print]

Gagnoux-Palacios L¹, Awina H², Audebert S³, Rossin A², Mondin M², Borgese F², Planas-Botey C², Mettouchi A⁴, Borg JP^3,5, Hueber AO⁶.

Author information

1. Université Côte d’Azur, Centre National de la Recherche Scientifique, Inserm, Institute de Biologie Valrose, Nice, France gagnoux@unice.fr.
2. Université Côte d’Azur, Centre National de la Recherche Scientifique, Inserm, Institute de Biologie Valrose, Nice, France.
3. Aix Marseille Université, Centre National de la Recherche Scientifique, Inserm, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, Marseille Proteomics, Marseille, France.
4. Institut Pasteur, Département de Microbiologie, Unité des Toxines Bactériennes, Université Paris Descartes, Paris, France.
5. Centre de Recherche en Cancérologie de Marseille, Cell Polarity, Cell Signaling, and Cancer, Equipe Labellisée Ligue Contre le Cancer, Aix Marseille Université, Centre National de la Recherche Scientifique, Inserm, Institut Paoli-Calmettes, Marseille, France.
6. Université Côte d’Azur, Centre National de la Recherche Scientifique, Inserm, Institute de Biologie Valrose, Nice, France hueber@unice.fr.

Abstract

Finely tuned regulation of epithelial cell death maintains tissue integrity and homeostasis. At the cellular level, life and death decisions are controlled by environmental stimuli such as the activation of death receptors. We show that cell polarity and adherens junction formation prevent proapoptotic signals emanating from the Fas death receptor. Fas is sequestered in E-cadherin actin-based adhesion structures that are less able to induce downstream apoptosis signaling. Using a proteomic-based approach, we find that the polarity molecule Dlg1 interacts with the C-terminal PDZ-binding site in Fas and that this interaction decreases formation of the death-inducing complex upon engagement with Fas ligand (FasL), thus acting as an additional cell death protection mechanism. We propose that E-cadherin and Dlg1 inhibit FasL-induced cell death by two complementary but partially independent mechanisms that help to maintain epithelial homeostasis by protecting normal polarized epithelia from apoptosis. When polarity is lost, the Fas-cadherin-Dlg1 antiapoptotic complex is disrupted, and FasL can promote the elimination of compromised nonpolarized cells.

PMID: 30242034
DOI: 10.1083/jcb.201805071