RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome

Zhang, Yingying; Su, Sheng Sean; Zhao, Shubo; Yang, Zhentao; Zhong, Chuan Qi; Chen, Xin; Cai, Qixu; Yang, Zhang Hua; Huang, Deli; Wu, Rui; Han, Jiahuai

doi:10.1038/ncomms14329

Cited by 372 publications

(331 citation statements)

References 49 publications

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“…In addition, transient phosphorylation of RIPK1 at Ser 25 by IKKs prevents its dissociation from complex‐I, and suppresses its Ser 166 ‐autophosphorylation‐dependent association with FADD to initiate formation of complex‐II/necrosome which functions as transcription‐independent players in TNF‐induced cell death . The kinase activity of RIPK1 is required for activation of RIPK3 that plays an essential role in necroptosis induction . Thus, discovery of small molecules regulating RIPK1 phosphorylation provides a basic research tool and substantiates the overall importance of early cell death checkpoint controlling apoptosis and necroptosis.…”

Section: Discussionmentioning

confidence: 95%

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

et al. 2020

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In tumor necrosis factor (TNF) signaling, phosphorylation and activation of receptor interacting protein kinase 1 (RIPK1) by upstream kinases is an essential checkpoint in the suppression of TNF‐induced cell death. Thus, discovery of pharmacological agents targeting RIPK1 may provide new strategies for improving the therapeutic efficacy of TNF. In this study, we found that 3‐O‐acetylrubianol C (3AR‐C), an arborinane triterpenoid isolated from Rubia philippinesis, promoted TNF‐induced apoptotic and necroptotic cell death. To identify the molecular mechanism, we found that in mouse embryonic fibroblasts, 3AR‐C drastically upregulated RIPK1 kinase activity by selectively inhibiting IKKβ. Notably, 3AR‐C did not interfere with IKKα or affect the formation of the TNF receptor1 (TNFR1) complex‐I. Moreover, in human cancer cells, 3AR‐C was only sufficient to sensitize TNF‐induced cell death when c‐FLIPL expression was downregulated to facilitate the formation of TNFR1 complex‐II and necrosome. Taken together, our study identified a novel arborinane triterpenoid 3AR‐C as a potent activator of TNF‐induced cell death via inhibition of IKKβ phosphorylation and promotion of the cytotoxic potential of RIPK1, thus providing a rationale for further development of 3AR‐C as a selective IKKβ inhibitor to overcome TNF resistance in cancer therpay.

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Section: Discussionmentioning

confidence: 95%

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

et al. 2020

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“…A second possibility is that the necroptotic signal generates a local burst of reactive oxygen species (ROS), which could induce oxidation of MLKL. A recent report demonstrated that upon necroptosis induction mitochondria ROS promoted RIPK1 autophosphorylation and RIPK3 recruitment (43). It is possible that the same mitochondria ROS could regulate MLKL disulfide bond formation and polymerization.…”

Section: Discussionmentioning

confidence: 99%

MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

Liu

Johnston

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

124

120

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Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α-induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

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“…Substantial evidence accumulated to show that reactive oxygen species (ROS) have long been considered to be a driving force for necroptosis [34-36]. A recent study showed that mitoROS promoted RIP1 autophosphorylation via modification of three crucial cysteine residues, and this phosphorylation event allowed efficient recruitment of RIP3 to RIP1 to form a functional necrosome for TNF-induced necroptosis [37]. In accordance with previous studies, we found that PM exposure induced mitoROS, and mitoROS mediated PM-induced necroptosis in HBE cells.…”

Section: Discussionmentioning

confidence: 99%

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Luo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Necroptosis, a form of programmed necrosis, is involved in the pathologic process of several kinds of pulmonary diseases. However, the role of necroptosis in particulate matter (PM)–induced pulmonary injury remains unclear. The objective of this study is to investigate the involvement of necroptosis in the pathogenesis of PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction, both in vitro and in vivo. Methods: PM was administered into human bronchial epithelial (HBE) cells or mouse airways, and the inflammatory response and mucus production were assessed. The mRNA expressions of IL6, IL8 and MUC5AC in HBE cells and Cxcl1, Cxcl2, and Gm-csf in the lung tissues were detected by quantitative real-time RT-PCR. The secreted protein levels of IL6 and IL8 in culture supernatants and Cxcl1, Cxcl2, and Gm-csf in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). We used Western blot to measure the protein expressions of necroptosis-related proteins (RIPK1, RIPK3, and Phospho-MLKL), NF-κB (P65 and PP65), AP-1 (P-c-Jun and P-c-Fos) and MUC5AC. Cell necrosis and mitochondrial ROS were detected using flow cytometry. In addition, pathological changes and scoring of lung tissue samples were monitored using hemoxylin and eosin (H&E), periodic acid-schiff (PAS) and immunohistochemistry staining. Results: Our study showed that PM exposure induced RIP and MLKL-dependent necroptosis in HBE cells and in mouse lungs. Managing the necroptosis inhibitor Necrostatin-1 (Nec-1) and GSK’872, specific molecule inhibitors of necroptosis, markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells. Similarly, administering Nec-1 significantly reduced airway inflammation and mucus hyperproduction in PM-exposed mice. Mechanistically, we found PM–induced necroptosis was mediated by mitochondrial reactive oxygen species-dependent early growth response gene 1, which ultimately promoted inflammation and mucin expression through nuclear factor κB and activator protein-1 pathways, respectively. Conclusions: Our results demonstrate that necroptosis is involved in the pathogenesis of PM–induced pulmonary inflammation and mucus hyperproduction, and suggests that it may be a novel target for treatment of airway disorders or disease exacerbations with airborne particulate pollution.

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RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome

Cited by 372 publications

References 49 publications

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

3‐O‐acetylrubianol C (3AR‐C) induces RIPK1‐dependent programmed cell death by selective inhibition of IKKβ

MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

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