RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

Rajput, Akhil; Kovalenko, Andrew; Богданов, Константин; Yang, Seung‐Hoon; Kang, Tae-Bong; Kim, Jin‐Chul; Du, Jianfang; Wallach, David

doi:10.1016/j.immuni.2010.12.018

Cited by 183 publications

(179 citation statements)

References 32 publications

(48 reference statements)

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“…2 B and C). A mutually nonexclusive possibility is that the absence of Nt-arginylation in ATE1-deficient mice not only augments the RIPK1/caspase-8 positive feedback but also increases, through a mechanism to be understood, the TNFα-induced processive degradation of fulllength RIPK1, a conditionally short-lived protein (6,33,36). In contrast to results with ATE1-deficient mouse tissues (Fig.…”

Section: Partial Ablations Of the Arg/n-end Rule Pathway Make Cellsmentioning

confidence: 85%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

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

123

195

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In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL XL , Arg-BIM EL , Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

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Section: Partial Ablations Of the Arg/n-end Rule Pathway Make Cellsmentioning

confidence: 85%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

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

123

195

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“…A recent study has shown RIP1 to be recruited to the RIG-1 mitochondrial complex with ubiquitination of RIP1 serving to provide docking sites for key signalling molecules such as the IKK complex that activates NFkB. 120 However, RIP1 can also facilitate recruitment of caspase 8 to the complex, resulting in the cleavage of RIP1 and the generation of an inhibitory RIP1 fragment that represses RIG-I-induced activation of IRF3. Thus RIP1 is a key regulator of the temporal expression of virus-responsive genes.…”

Section: Rip Kinases and Nucleic Acid Sensingmentioning

confidence: 99%

RIP kinases: key decision makers in cell death and innate immunity

et al. 2014

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“…23,24 Therefore, we investigated whether RIP-1 was involved in the death of c-FLIP L -deficient T lymphocytes. Autophagy is enhanced in c-FLIP L À / À T lymphocytes.…”

Section: Cellular Caspase 8 (Flice)-like Inhibitory Protein (C-flip) mentioning

confidence: 99%

“…24 Studies in human fibroblast cell lines showed that caspase 8 mediated the cleavage of RIP-1 to produce an inhibitory RIP-1 fragment. 23 It is possible that a similar inhibitory mechanism may occur in T lymphocytes: c-FLIP L may regulate RIP-1 activity by recruiting RIP-1 to the DISC for caspase 8-dependent degradation. In this model, without c-FLIP L , the recruitment of RIP-1 is blocked.…”

Section: Necroptosis In C-flip L -Deficient T Cells Involves Reactivementioning

confidence: 99%

A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

2012

Cell Death Differ

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Caspase 8 plays a dual role in the survival of T lymphocytes. Although active caspase 8 mediates apoptosis upon death receptor signaling, the loss of caspase 8 activity leads to receptor-interacting protein (RIP)-1/RIP-3-dependent necrotic cell death (necroptosis) upon TCR activation. The anti-apoptotic protein c-FLIP (cellular caspase 8 (FLICE)-like inhibitory protein) suppresses death receptor-induced caspase 8 activation. Moreover, recent findings suggest that c-FLIP is also involved in inhibiting necroptosis and autophagy. It remains unclear whether c-FLIP protects primary T lymphocytes from necroptosis or regulates the threshold at which autophagy occurs. Here, we used a c-FLIP isoform-specific conditional deletion model to show that c-FLIP L -deficient T cells underwent RIP-1-dependent necroptosis upon TCR stimulation. Interestingly, although previous studies have only described necroptosis in the absence of caspase 8 activity, we found that pro-apoptotic caspase 8 activity and apoptosis were also enhanced in c-FLIP L -deficient T lymphocytes. Furthermore, c-FLIP L -deficient T cells exhibited enhanced autophagy, which served a cytoprotective function. Together, these findings indicate that c-FLIP L plays an important antinecroptotic role and is a key regulator of apoptosis, autophagy, and necroptosis in T lymphocytes.

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RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

Cited by 183 publications

References 32 publications

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

RIP kinases: key decision makers in cell death and innate immunity

A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

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