Characteristic ERK1/2 signaling dynamics distinguishes necroptosis from apoptosis
François Sipieter,
Benjamin Cappe,
Aymeric Leray,
Elke De Schutter,
Jolien Bridelance,
Paco Hulpiau,
Guy Van Camp,
Wim Declercq,
Laurent Héliot,
Pierre Vincent,
Peter Vandenabeele,
Franck B. Riquet
Affiliations
François Sipieter
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium; Université de Lille, Lille, France
Benjamin Cappe
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium
Aymeric Leray
Laboratoire Interdisciplinaire Carnot De Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, France
Elke De Schutter
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, Edegem, 2650 Antwerp, Belgium
Jolien Bridelance
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium
Paco Hulpiau
Data Mining and Modeling for Biomedicine (DaMBi), VIB Center for Inflammation Research, Ghent, Belgium
Guy Van Camp
Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, Edegem, 2650 Antwerp, Belgium; Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, Wilrijk, 2610 Antwerp, Belgium
Wim Declercq
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium
Laurent Héliot
Team Biophotonique Cellulaire Fonctionnelle, Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM), CNRS UMR 8523, 59655 Villeneuve d’Ascq, France
Pierre Vincent
Sorbonne Université, CNRS, Neurobiology of Adaptative Processes, UMR8256, 75005 Paris, France
Peter Vandenabeele
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium
Franck B. Riquet
Molecular Signaling and Cell Death Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Technologiepark 71, Zwijnaarde, 9052 Ghent, Belgium; Université de Lille, Lille, France; Corresponding author
Summary: ERK1/2 involvement in cell death remains unclear, although many studies have demonstrated the importance of ERK1/2 dynamics in determining cellular responses. To untangle how ERK1/2 contributes to two cell death programs, we investigated ERK1/2 signaling dynamics during hFasL-induced apoptosis and TNF-induced necroptosis in L929 cells. We observed that ERK1/2 inhibition sensitizes cells to apoptosis while delaying necroptosis. By monitoring ERK1/2 activity by live-cell imaging using an improved ERK1/2 biosensor (EKAR4.0), we reported differential ERK1/2 signaling dynamics between cell survival, apoptosis, and necroptosis. We also decrypted a temporally shifted amplitude- and frequency-modulated (AM/FM) ERK1/2 activity profile in necroptosis versus apoptosis. ERK1/2 inhibition, which disrupted ERK1/2 signaling dynamics, prevented TNF and IL-6 gene expression increase during TNF-induced necroptosis. Using an inducible cell line for activated MLKL, the final executioner of necroptosis, we showed ERK1/2 and its distinctive necroptotic ERK1/2 activity dynamics to be positioned downstream of MLKL.
