Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

Lucie Laurien, Masahiro Nagata, Hannah Schünke, Tom Delanghe, Janica L. Wiederstein, Snehlata Kumari, Robin Schwarzer, Teresa Corona, Marcus Krüger, Mathieu J. M. Bertrand, Vangelis Kondylis and Manolis Pasparakis ()
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Lucie Laurien: University of Cologne
Masahiro Nagata: University of Cologne
Hannah Schünke: University of Cologne
Tom Delanghe: VIB Center for Inflammation Research
Janica L. Wiederstein: University of Cologne
Snehlata Kumari: University of Cologne
Robin Schwarzer: University of Cologne
Teresa Corona: University of Cologne
Marcus Krüger: University of Cologne
Mathieu J. M. Bertrand: VIB Center for Inflammation Research
Vangelis Kondylis: University of Cologne
Manolis Pasparakis: University of Cologne

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

Date: 2020
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DOI: 10.1038/s41467-020-15466-8

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