The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Webster, Joshua D.; Vucic, Domagoj

doi:10.3389/fcell.2020.00365

Cited by 182 publications

(148 citation statements)

References 150 publications

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“…In addition, RIP1 restricts ZBP1‐mediated necroptosis by interfering with RHIM‐mediated interaction of ZBP1 and RIP3 (Lin et al , 2016; Newton et al , 2016b). The interplay of apoptosis and necroptosis is apparent in many inflammatory in vivo models where they are frequently concomitantly activated (Webster & Vucic, 2020). This is not surprising given that majority of signaling proteins are common to both pathways, and the balance of expression or activation of critical factors (RIP3, caspase‐8) can tip the balance in favor of apoptosis or necroptosis.…”

Section: Introductionmentioning

confidence: 99%

Cell death pathways: intricate connections and disease implications

Kist¹,

Vucic²

2021

The EMBO Journal

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191

140

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Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their respective pathway(s). In addition to the three best characterized pathways—apoptosis, necroptosis, and pyroptosis—other forms of regulated cell death including autophagy‐dependent cell death (ADCD), mitochondrial permeability transition pore (MPTP)‐mediated necrosis, parthanatos, NETosis and ferroptosis, and their relevance for organismal homeostasis are becoming better understood. Importantly, it is increasingly clear that none of these pathways operate alone. Instead, a more complex picture is emerging with many pathways sharing components and signaling principles. Finally, a number of cell death regulators are implicated in human diseases and represent attractive therapeutic targets. Therefore, better understanding of physiological and mechanistic aspects of cell death signaling should yield improved reagents for addressing unmet medical needs.

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Section: Introductionmentioning

confidence: 99%

Cell death pathways: intricate connections and disease implications

Kist¹,

Vucic²

2021

The EMBO Journal

Self Cite

191

140

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“…TNFα triggered pro-inflammatory gene expression through the activation of both NF-κB and MAP kinase pathways ( Kyriakis and Avruch, 2001 ; Zelová and Hošek, 2013 ; Webster and Vucic, 2020 ). Therefore, we determined the two main signalling cascades activated by TNFα after TNFAIP1 silencing.…”

Section: Discussionmentioning

confidence: 99%

Cullin3-TNFAIP1 E3 Ligase Controls Inflammatory Response in Hepatocellular Carcinoma Cells via Ubiquitination of RhoB

Liu

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Rho family GTPase RhoB is the critical signaling component controlling the inflammatory response elicited by pro-inflammatory cytokines. However, the underlying mechanisms of RhoB degradation in inflammatory response remain unclear. In this study, for the first time, we identified that TNFAIP1, an adaptor protein of Cullin3 E3 ubiquitin ligases, coordinated with Cullin3 to mediate RhoB degradation through ubiquitin proteasome system. In addition, we demonstrated that downregulation of TNFAIP1 induced the expression of pro-inflammatory cytokines IL-6 and IL-8 in TNFα-stimulated hepatocellular carcinoma cells through the activation of p38/JNK MAPK pathway via blocking RhoB degradation. Our findings revealed a novel mechanism of RhoB degradation and provided a potential strategy for anti-inflammatory intervention of tumors by targeting TNFAIP1-RhoB axis.

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“…Proper regulation of cell death is critical for the development and homeostasis in metazoans. Dysregulation of cell death pathways is associated with a number of human diseases, including cancer, tissue damage/inflammation, and neurodegeneration 1 , 2 . The best-known form of regulated cell death is apoptosis, which relies on the activation of cysteine proteases called caspases 3 .…”

Section: Introductionmentioning

confidence: 99%

Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury

Stark¹,

Goncharov²,

Varfolomeev³

et al. 2021

Cell Death Dis

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RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders.

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The Balance of TNF Mediated Pathways Regulates Inflammatory Cell Death Signaling in Healthy and Diseased Tissues

Cited by 182 publications

References 150 publications

Cell death pathways: intricate connections and disease implications

Cell death pathways: intricate connections and disease implications

Cullin3-TNFAIP1 E3 Ligase Controls Inflammatory Response in Hepatocellular Carcinoma Cells via Ubiquitination of RhoB

Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury

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