Lyn attenuates cisplatin-induced acute kidney injury by inhibition of RIPK1-mediated apoptosis and necroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Juan Tang
PROVIDER: PXD078460 | iProX | Sat May 16 00:00:00 GMT+01:00 2026
REPOSITORIES: iProX
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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.
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Project description:Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and premature aging. Accumulation of progerin, a toxic isoform of lamin A, or prelamin A, the precursor protein of lamin A, is the major underlying cause of premature aging syndromes. However, the molecular mechanism that mediates premature aging remains poorly defined. Here we report that the accumulation of farnesylated forms of prelamin A at the nuclear lamina triggers RIPK1 kinase-dependent signaling that leads to inflammation and RIPK3-mediated necroptosis in multiple tissues of a mouse model of accelerated aging (Zmpste24-/- mice). We show that prelamin A recruits RIPK1 in the nucleus to facilitate its activation in response to TNFα stimulation. Inhibition of prelamin A farnesylation prevents its accumulation at the nuclear envelope, and consequently reduces RIPK1 activation and necroptosis. The causality of RIPK1-driven necroptosis and inflammation in premature aging was demonstrated by genetic inactivation of RIPK1 or knockout of RIPK3, which prevented the premature degeneration of multiple tissues and organs in Zmpste24-/- mice and significantly extended their longevity. Our findings provide in vivo proof of principle for the feasibility of inhibition of RIPK1 kinase to slow down the progression of physiological and pathological aging.
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Project description: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.
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Project description:Phase separation is a vital mechanism that mediates the formation of biomolecular condensates and their functions. Necroptosis is a lytic form of programmed cell death mediated by RIPK1, RIPK3 and MLKL downstream of TNFR1 and other receptors and has been implicated in mediating many human diseases. However, whether necroptosis is regulated by phase separation is not yet known. Here, we show that upon the induction of necroptosis and recruitment by the adaptor protein TAX1BP1, PARP5A and its binding partner RNF146 are rapidly induced to form liquid-like condensates by multivalent interactions to perform poly ADP-ribosylation (PARylation) and PARylation-dependent ubiquitination (PARdU) of activated RIPK1. We show that PARdU predominantly occurs on the K376 residue of RIPK1, which promotes proteasomal degradation of kinase-activated RIPK1 to restrain the formation of necrosomes. This modification is essential in vivo, as PARP5A deficiency sensitized mice to TNFα-induced lethal shock in a RIPK1kinase-dependent manner. Our data demonstrate that PARdU on K376 RIPK1 provides an alternative cell death checkpoint mediated by phase separation-dependent control of necroptosis by PARP5A and RNF146.
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Project description:Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl, and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many mucosal epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl. Intriguingly, expression of ZBP1 was elevated in Casp8-/- Tnfr1-/- embryos prior to their succumbing to aberrant necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because rare Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. Of note, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5-7 weeks of being born, which is not seen in Casp8-/- Ripk1-/- Trif-/- Zbp1-/-, Casp8-/- Ripk3-/-, or Casp8-/- Mlkl-/- mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.
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