More to Life than NF-κB in TNFR1 Signaling

Ting, Adrian T.; Bertrand, Mathieu J.M.

doi:10.1016/j.it.2016.06.002

Cited by 219 publications

(220 citation statements)

References 78 publications

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“…The participation of IKKβ in TNF‐mediated cell death could occur at a point of either NF‐κB‐dependent or ‐independent . In this study, we found that 3AR‐C sensitized RIPK1‐dependent apoptosis and necroptosis upon TNFR1 ligation by inhibiting IKKβ.…”

Section: Discussionmentioning

confidence: 54%

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: 54%

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

et al. 2020

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“…Depending on the cellular conditions, the enzymatic activity of RIPK1 has been reported capable of mediating apoptosis or necroptosis, a regulated form of necrosis with RIPK3 and MLKL as core components. 40, 41 We found that WT mice with ConA-induced liver injuries exhibited only few caspase-3-positive hepatocytes, and that pan-caspase inhibition by Q-VD-OPh failed to protect these mice from ConA-induced hepatitis, supportive of necroptosis induction. Nevertheless, because a switch from apoptosis to necroptosis has been reported in hepatocytes upon caspases inactivation, 42, 43 future works using hepatocytes-deficient RIPK3 or MLKL mice will help ruling out the occurrence of RIPK1 kinase-dependent apoptosis during ConA hepatitis.…”

Section: Discussionmentioning

confidence: 78%

RIPK1 protects from TNF-α-mediated liver damage during hepatitis

et al. 2016

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Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-α) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-α-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-KO), to characterize the role of RIPK1 and TNF-α in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1LPC-KO mice challenged with ConA, TNF-α triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-κB activation, as well as TNF-dependent, but canonical NF-κB-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases.

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“…Nevertheless, our results raise the question of why the inhibition of NEMO but not RIP1 polyubiquitination may be beneficial to MCV. TNF-TNFR1 interactions possess the capacity to trigger either NF-B activation, apoptosis, or necroptosis (19,54). The ubiquitination status of RIP1 can control this outcome (23,51,55,56).…”

Section: Discussionmentioning

confidence: 99%

Molluscum Contagiosum Virus MC159 Abrogates cIAP1-NEMO Interactions and Inhibits NEMO Polyubiquitination

Biswas

Shisler

2017

J Virol

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Molluscum contagiosum virus (MCV) is a dermatotropic poxvirus that causes benign skin lesions. MCV lesions persist because of virally encoded immune evasion molecules that inhibit antiviral responses. The MCV MC159 protein suppresses NF-B activation, a powerful antiviral response, via interactions with the NF-B essential modulator (NEMO) subunit of the IB kinase (IKK) complex. Binding of MC159 to NEMO does not disrupt the IKK complex, implying that MC159 prevents IKK activation via an as-yet-unidentified strategy. Here, we demonstrated that MC159 inhibited NEMO polyubiquitination, a posttranslational modification required for IKK and downstream NF-B activation. Because MCV cannot be propagated in cell culture, MC159 was expressed independent of infection or during a surrogate vaccinia virus infection to identify how MC159 prevented polyubiquitination. Cellular inhibitor of apoptosis protein 1 (cIAP1) is a cellular E3 ligase that ubiquitinates NEMO. Mutational analyses revealed that MC159 and cIAP1 each bind to the same NEMO region, suggesting that MC159 may competitively inhibit cIAP1-NEMO interactions. Indeed, MC159 prevented cIAP1-NEMO interactions. MC159 also diminished cIAP1-mediated NEMO polyubiquitination and cIAP1-induced NF-B activation. These data suggest that MC159 competitively binds to NEMO to prevent cIAP1-induced NEMO polyubiquitination. To our knowledge, this is the first report of a viral protein disrupting NEMO-cIAP1 interactions to strategically suppress IKK activation. All viruses must antagonize antiviral signaling events for survival. We hypothesize that MC159 inhibits NEMO polyubiquitination as a clever strategy to manipulate the host cell environment to the benefit of the virus. IMPORTANCE Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes persistent skin neoplasms. The persistence of MCV has been attributed to viral downregulation of host cell immune responses such as NF-B activation. We show here that the MCV MC159 protein interacts with the NEMO subunit of the IKK complex to prevent NEMO interactions with the cIAP1 E3 ubiquitin ligase. This interaction correlates with a dampening of cIAP1 to polyubiquitinate NEMO and to activate NF-B. This inhibition of cIAP1-NEMO interactions is a new viral strategy to minimize IKK activation and to control NEMO polyubiquitination. This research provides new insights into mechanisms that persistent viruses may use to cause long-term infection of host cells.

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More to Life than NF-κB in TNFR1 Signaling

Cited by 219 publications

References 78 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

RIPK1 protects from TNF-α-mediated liver damage during hepatitis

Molluscum Contagiosum Virus MC159 Abrogates cIAP1-NEMO Interactions and Inhibits NEMO Polyubiquitination

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