Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation
Hailin Tu1, Weihang Xiong1,2, Jie Zhang1
1Institute for Immunology, School of Medicine, Tsinghua University, Beijing, China.
Abstract:
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.
Insights
Tyrosine phosphorylation of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by JAK1 and SRC suppresses inflammation and cell death. Loss of this phosphorylation in mice causes severe systemic inflammation and emergency hematopoiesis.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of inflammatory and cell death pathways.
- While serine/threonine phosphorylation of RIPK1 is known to suppress its kinase activity, the role of tyrosine phosphorylation remains unexplored.
Purpose of the Study:
- To investigate the role of tyrosine phosphorylation in regulating RIPK1 activity and its impact on cell death and inflammation.
- To identify the specific tyrosine kinases involved in RIPK1 phosphorylation.
Main Methods:
- Investigated RIPK1 phosphorylation using biochemical assays.
- Utilized a mouse model with a specific mutation preventing RIPK1 tyrosine phosphorylation (Ripk1Y383F/Y383F).
- Analyzed the effects of this mutation on TNF-induced cell death, inflammation, and hematopoiesis, and tested interventions like RIPK1 kinase inhibition and genetic deletions.
Main Results:
- Identified Janus kinase 1 (JAK1) and SRC as tyrosine kinases that phosphorylate RIPK1 at Y384, suppressing TNF-induced cell death.
- Ripk1Y383F/Y383F mice exhibited systemic inflammation and emergency hematopoiesis due to enhanced RIPK1 kinase activation and TNF-induced apoptosis/necroptosis.
- Impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2) were observed in the mutant mice.
- Systemic inflammation and emergency hematopoiesis were ameliorated by RIPK1 kinase inhibition and prevented by upstream pathway genetic deletions.
Conclusions:
- Tyrosine phosphorylation of RIPK1 is a critical regulatory mechanism that limits RIPK1 kinase activity, thereby suppressing cell death and inflammation.
- This finding reveals a novel layer of RIPK1 regulation with significant implications for understanding and potentially treating inflammatory diseases.
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