Journal Article

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

Bertrand, Mathieu J. M., Schünke, Hannah, Delanghe, Tom, Wiederstein, Janica L., Krüger, Marcus, Corona, Teresa, Schwarzer, Robin, Pasparakis, Manolis, Nagata, Masahiro, Laurien, Lucie, Kondylis, Vangelis, Kumari, Snehlata

2020

Overview

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. Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses. Here the authors show that autophosphorylation at Ser166 is required for RIPK1-mediated cell death and inflammation in mouse models of inflammatory pathologies, making Ser166 phosphorylation a possible biomarker for RIPK1-mediated inflammatory diseases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/2 / 13/51 / 14 / 14/63 / 38/39 / 42/41 / 631/80/82/23 / 631/80/82/2344 / 64/60 / 82/51 / 82/58 / Activation / Alanine Transaminase - metabolism / Animal models / Animals / Apoptosis / Biomarkers / Bone Marrow Cells - cytology / Cell death / Colitis - pathology / Genotype / Hepatitis - pathology / Humanities and Social Sciences / Inflammation / Inflammation - metabolism / Inflammation - pathology / Inflammatory diseases / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Macrophages - metabolism / Mice, Inbred C57BL / Mortality / multidisciplinary / Mutation - genetics / Necroptosis / Neoplasms - pathology / Pathogenesis / Phosphorylation / Phosphoserine - metabolism / Protein kinase / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Receptors / Science / Science (multidisciplinary) / Sepsis - pathology / Signaling / Skin - pathology / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha