GRIM-19 Mediated Translocation of STAT3 to Mitochondria is Necessary for TNF Induced Necroptosis.

Shulga, Nataly; Pastorino, John G.

doi:10.1242/jcs.103093

Cited by 95 publications

(92 citation statements)

References 40 publications

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“…We demonstrated previously that during TNFa-induced necroptosis of L929 cells, the translocation of a complex of Stat3 and Grim-19 to the mitochondria occurs and brings about mitochondrial injury and loss of cell viability (Shulga and Pastorino, 2012). We wanted to determine whether a similar mechanism was applicable in TNFa-induced necroptosis of hepatocytes exposed to fructose and ethanol.…”

Section: Tnfa Induces Binding Of Stat3-grim-19 To Mitoneetmentioning

confidence: 98%

“…It has recently been demonstrated that RIPK-3 is required for ethanol induced liver injury (Roychowdhury et al, 2013). We have demonstrated that TNFa-induced necroptosis in some instances is brought about by RIPK-1-dependent phosphorylation of a STAT3-Grim-19 complex, which upon phosphorylation, translocates to the mitochondria where it induces production of reactive oxygen species (ROS) and onset of the transition to mitochondrial permeability (Shulga and Pastorino, 2012). However, how the STAT3-GRIM-19 complex induces ROS production at the mitochondria is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Shulga

Pastorino

2013

Journal of Cell Science

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Fructose and ethanol are metabolized principally in the liver and are both known to contribute to the development of hepatic steatosis that can progress to hepatic steatohepatitis. The present study indentifies a synergistic interaction between fructose and ethanol in promoting hepatocyte sensitivity to TNFa-induced necroptosis. Concurrent exposure to fructose and ethanol induces the overexpression of the CDGSH iron-sulfur domain-containing protein 1 (CISD1 or mitoneet), which is localized to the outer mitochondrial membrane. The increased expression of mitoneet primes the hepatocyte for TNFa-induced cytotoxicity. Treatment with TNFa induces the translocation of a Stat3-Grim-19 complex to the mitochondria, which binds to mitoneet and promotes the rapid release of its 2Fe-2S cluster, causing an accumulation of mitochondrial iron. The dramatic increase of mitochondrial iron provokes a surge in formation of reactive oxygen species, resulting in mitochondrial injury and cell death. Additionally, mitoneet is constitutively expressed at high levels in L929 fibrosarcoma cells and is required for L929 cells to undergo TNFa-induced necroptosis in the presence of caspase inhibition, indicating the importance of mitoneet to the necroptotic form of cell death.

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Section: Tnfa Induces Binding Of Stat3-grim-19 To Mitoneetmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Shulga

Pastorino

2013

Journal of Cell Science

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“…During TNF-induced necroptosis, STAT3 undergoes Ser 727 phosphorylation, which is dependent on RIP1 expression and activation (37). Our previous reports (20,21) and the present study suggest that Y14 is involved in TNF-a-mediated signals through at least two possible mechanisms: enhancement of the association between TRADD and RIP1 and augmentation of NF-kB modification via STAT3.…”

Section: Discussionsupporting

confidence: 57%

Y14 Positively Regulates TNF-α–Induced NF-κB Transcriptional Activity via Interacting RIP1 and TRADD Beyond an Exon Junction Complex Protein

Togi

Shiga

Muromoto

et al. 2013

The Journal of Immunology

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Although Y14 is known to be a component of the exon junction complex, we previously reported that Y14 regulates IL-6–induced STAT3 activation. In this study, we showed that endogenous Y14 positively regulated TNF-α–induced IL-6 expression in HeLa cells. Small interfering RNA–mediated Y14-knockdown reduced TNF-α–induced and NF-κB–mediated transcriptional activity, phosphorylation/degradation of IκBα, and nuclear localization of NF-κB/p65. As in the case of IL-6 stimuli, Y14 enhanced TNF-α–induced STAT3 phosphorylation, which is important for its nuclear retention. However, our manipulation of Y14 expression indicated that it is involved in TNF-α–induced IL-6 expression via both STAT3-dependent and -independent mechanisms. We screened signaling molecules in the TNF-α–NF-κB pathway and found that Y14 endogenously associated with receptor-interacting protein 1 (RIP1) and TNFR-associated death domain (TRADD). Overexpression of RIP1, but not TRADD, restored TNF-α–induced NF-κB activation in Y14-knockdown cells, and Y14 overexpression restored TNF-α–induced NF-κB activation in TRADD-knockdown cells, but not in RIP1-knockdown cells, indicating that Y14 lies downstream of TRADD and upstream of RIP1. Of importance, Y14 significantly enhanced the binding between RIP1 and TRADD, and this is a possible new mechanism for Y14-mediated modification of TNF-α signals. Although Y14 associates with MAGOH in the exon junction complex, Y14’s actions in the TNF-α–NF-κB pathway are unlikely to require MAGOH. Therefore, Y14 positively regulates signals for TNF-α–induced IL-6 production at multiple steps beyond an exon junction complex protein.

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“…Other biochemical activities that have been implicated in necroptotic cell death, including activation of phospholipase activity, 46 phosphorylation of signal transducer and activator of transcription 3 47 and mitochondrial membrane pore opening, regulated through cyclophilin D. 48 Very recently, involvement of cyclophilin D in necroptosis has been shown to be RIP3-dependent and that it can be inhibited by cyclosporin A. 49 This suggests that the neuroprotective effect provided by cyclosporin A that has been used previously to treat rats with diabetic retinopathy 50 and that can prevent the loss of therapeutic cell transplants from dying in the retina 51 could be in part the result of inhibiting RIP3-dependent necroptosis rather than due to its immunosuppressive activity alone.…”

Section: Discussionmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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GRIM-19 Mediated Translocation of STAT3 to Mitochondria is Necessary for TNF Induced Necroptosis.

Cited by 95 publications

References 40 publications

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Y14 Positively Regulates TNF-α–Induced NF-κB Transcriptional Activity via Interacting RIP1 and TRADD Beyond an Exon Junction Complex Protein

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

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