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Quantitative analysis of phosphoproteome in necroptosis reveals a role of TRIM28 phosphorylation in promoting necroptosis-induced cytokine production

ABSTRACT: Necroptosis is a form of regulated necrotic cell death which promotes inflammation. In cells undergoing necroptosis, the activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in necroptosis. However, the signaling pathways downstream of RIPK1 kinase in necroptosis and how RIPK1 kinase activation controls inflammatory response induced by necroptosis are still largely unknown. Here we quantitatively measured the temporal dynamics of over 7000 confident phosphosites during necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in necroptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171214 | GEO | 2021/04/01

REPOSITORIES: GEO

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ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1

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2021-10-26 | GSE176422 | GEO

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2021-04-28 | PXD015537 | Pride

Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

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2022-09-19 | GSE208744 | GEO

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2021-05-27 | GSE157018 | GEO

Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis [II]

2021-05-27 | GSE166936 | GEO

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2023-09-15 | GSE195455 | GEO

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2023-09-15 | GSE195457 | GEO

O-GlcNAcylation of RIPK1 Rescues Red Blood Cells from Necroptosis

Project description:Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which O-GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that O- GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that O- GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits 32 This is a provisional file, not the final typeset article phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in Ripk1 -/- MEFs. Thus, our study demonstrates that RIPK1 O-GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.

2023-06-06 | PXD042579 | Pride

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