1. Constitutive Interferon Attenuates RIPK1/3-Mediated Cytokine Translation
- Author
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Vladimir Ilyukha, Alexei Degterev, Wilson M. Connolly, Hayley I. Muendlein, Beiyun C. Liu, Nahum Sonenberg, Jodie R. Pietruska, Alexander Poltorak, Stephen A Schworer, Amy Y. Tang, Irina Smirnova, Joseph Sarhan, and Soroush Tahmasebi
- Subjects
0301 basic medicine ,Lipopolysaccharides ,medicine.medical_treatment ,Necroptosis ,Down-Regulation ,Cell Cycle Proteins ,mTORC1 ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,RIPK1 ,0302 clinical medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Kinase activity ,Protein kinase A ,Protein kinase B ,lcsh:QH301-705.5 ,Adaptor Proteins, Signal Transducing ,Inflammation ,EIF4E ,Macrophage Activation ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Cytokine ,Eukaryotic Initiation Factor-4E ,lcsh:Biology (General) ,Protein Biosynthesis ,Receptor-Interacting Protein Serine-Threonine Kinases ,Cytokines ,Female ,Interferons ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
SUMMARY Receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3) are well known for their capacity to drive necroptosis via mixed-lineage kinase-like domain (MLKL). Recently, RIPK1/3 kinase activity has been shown to drive inflammation via activation of MAPK signaling. However, the regulatory mechanisms underlying this kinase-dependent cytokine production remain poorly understood. In the present study, we establish that the kinase activity of RIPK1/3 regulates cytokine translation in mouse and human macrophages. Furthermore, we show that this inflammatory response is downregulated by type I interferon (IFN) signaling, independent of type I IFN-promoted cell death. Specifically, low-level constitutive IFN signaling attenuates RIPK-driven activation of cap-dependent translation initiation pathway components AKT, mTORC1, 4E-BP and eIF4E, while promoting RIPK-dependent cell death. Altogether, these data characterize constitutive IFN signaling as a regulator of RIPK-dependent inflammation and establish cap-dependent translation as a crucial checkpoint in the regulation of cytokine production., In Brief Balancing inflammatory responses is critical for host survival. Muendlein et al. show that constitutive type I IFN signaling inhibits translation machinery activated downstream of the kinase activity of RIPK1/3, preventing the production of a subset of inflammatory cytokines. This work identifies cap-dependent translation as a checkpoint in regulation of RIPK1/3-kinase-dependent inflammation., Graphical Abstract
- Published
- 2020