Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis

Weber, Kathrin; Roelandt, Ria; Bruggeman, Inge; Estornes, Yann; Vandenabeele, Peter

doi:10.1038/s42003-017-0007-1

Cited by 120 publications

(117 citation statements)

References 51 publications

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“…Nuclear translocation of RIPKs was reported in TNFαinduced necroptosis [48,49]. Our observations indicated that RIPKs translocated into the nucleus and bound to RARα by inhibition of Caspase-8 activity.…”

Section: Discussionsupporting

confidence: 60%

Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis

et al. 2019

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Among caspase family members, Caspase-8 is unique, with associated critical activities to induce and suppress death receptor-mediated apoptosis and necroptosis, respectively. Caspase-8 inhibits necroptosis by suppressing the function of receptor-interacting protein kinase 1 (RIPK1 or RIP1) and RIPK3 to activate mixed lineage kinase domain-like (MLKL). Disruption of Caspase-8 expression causes embryonic lethality in mice, which is rescued by depletion of either Ripk3 or Mlkl, indicating that the embryonic lethality is caused by activation of necroptosis. Here, we show that knockdown of Caspase-8 expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent on Ripk1 and Ripk3; however, the enhancement of RA-induced cell differentiation is independent of Mlkl and necrosome formation. RA treatment obviously enhanced the expression of RA-specific target genes having the retinoic acid response element (RARE) in their promoter regions to induce cell differentiation, and induced marked expression of RIPK1, RIPK3, and MLKL to stimulate necroptosis. Caspase-8 knockdown induced RIPK1 and RIPK3 to translocate into the nucleus and to form a complex with RA receptor (RAR), and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity to RARE than RAR without RIPK1 or RIPK3. In Caspase-8-deficient as well as Caspase-8-and Mlkl-deficient mouse embryos, the expression of RA-specific target genes was obviously enhanced. Thus, Caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo.

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Section: Discussionsupporting

confidence: 60%

Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis

et al. 2019

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“…Currently, the primary method for confirming necroptosis involves detection of the key molecules that control this process (i.e. RIP1, RIP3, and MLKL) [53,54]. RIP1/3 has been found to promote anti-metastatic outcomes by regulating oxidative stress to kill metastatic tumor cells [55,56].…”

Section: Discussionmentioning

confidence: 99%

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

et al. 2019

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Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the MYCN gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-L-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.

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“…It has been suggested that MLKL mediates disruption of plasma membrane permeability by activating ion channels or forming pore structures directly in the plasma membrane [25][26][27][28]. Although the key events of necroptosis are believed to happen in the cytosol, interestingly, nuclear translocation of RIPK3 and MLKL has been observed and seems to play a role in accelerating the necroptotic process [29,30].…”

Section: Necroptosis: a Type Of Programmed Necrosismentioning

confidence: 99%

Necroptosis, tumor necrosis and tumorigenesis

Liu

Jiao

2020

CST

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Necroptosis, known as programmed necrosis, is a form of caspase-independent, finely regulated cell death with necrotic morphology. Tumor necrosis, foci of necrotic cell death, occurs in advanced solid tumors and is often associated with poor prognosis of cancer patients. While it is well documented that apoptosis plays a key role in tumor regression and the inactivation of apoptosis is pivotal to tumor development, the role of necroptosis in tumorigenesis is still not fully understood as recent studies have reported both tumor-promoting and tumor-suppressing effects of necroptosis. In this short review, we will discuss some recent studies about the role of necroptosis in tumorigenesis and speculate the implications of these findings in future research and potential novel cancer therapy targeting necroptosis.

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Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis

Cited by 120 publications

References 51 publications

Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis

Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

Necroptosis, tumor necrosis and tumorigenesis

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