The 3'-untranslated regions of cytoskeletal muscle mRNAs inhibit translation by activating the double-stranded RNA-dependent protein kinase PKR

Nussbaum, Jean M

doi:10.1093/nar/30.5.1205

Cited by 44 publications

(36 citation statements)

References 44 publications

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“…In support of this hypothesis, we find that exogenously supplied dsRNA can activate PKR and trigger necrosis without need for mRNA transcription. Activation of PKR by cellular RNAs is not without precedent: the 3′-untranslated regions (UTRs) of several cytoskeletal and cytokine mRNAs have been shown to activate this kinase in various physiological contexts (22)(23)(24)(25)(26). Indeed, such endogenous mRNAs can activate PKR even more potently than dsRNA (27).…”

Section: Discussionmentioning

confidence: 99%

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

Thapa

Nogusa

Chen

et al. 2013

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

307

261

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Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral properties, but less is known about how they induce cell death. Here, we show that both type I (α/β) and type II (γ) IFNs induce precipitous receptor-interacting protein (RIP)1/RIP3 kinasemediated necrosis when the adaptor protein Fas-associated death domain (FADD) is lost or disabled by phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced necrosis proceeds via progressive assembly of a RIP1-RIP3 "necrosome" complex that requires Jak1/STAT1-dependent transcription, but does not need the kinase activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 to initiate necrosome formation and trigger necrosis. Although IFNs are powerful activators of necrosis when FADD is absent, these cytokines are likely not the dominant inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We also identify phosphorylation on serine 191 as a mechanism that disables FADD and collaborates with caspase inactivation to allow IFN-activated necrosis. Collectively, these findings outline a mechanism of IFN-induced RIP kinase-dependent necrotic cell death and identify FADD and caspases as negative regulators of this process.necroptosis | apoptosis I nterferons (IFNs) are pleiotropic cytokines classified into two primary groups, type I (predominantly α/β) and type II (γ). Both classes of IFNs exert their effects via similar Janus kinase (JAK)-signal transducers and activators of transcription (STAT)-dependent signaling cascades to induce the expression of over 500 genes (1). Such IFN-stimulated genes (ISGs) have been reasonably well characterized in the context of antiviral or immune-modulatory signaling, but less is known about how they collaborate to mediate the cytotoxic and antiproliferative effects of IFNs.Recent studies have shed light on a new form of regulated cell death that is activated when caspase-dependent apoptotic pathways are inhibited. This mode of necrotic cell death, sometimes called "necroptosis," requires the serine-threonine kinases receptor-interacting protein 1 (RIP1) and RIP3, and results from overproduction of reactive oxygen species (ROS) and eventual mitochondrial dysfunction (2, 3). Strict negative control of the pronecrotic kinases RIP1 and RIP3 are essential for several aspects of mammalian development and homeostasis, including immune cell proliferation and progression through embryogenesis (4). The proteins FADD, caspase 8, and c-FLIP represent three such negative regulators; in the absence of any of these molecules, the RIP kinases trigger inopportune necrosis, often with severe consequences for the host (4). The core necrosis machinery is thus carefully regulated to execute cell death only in specific contexts, but how this regulation is achieved and which other upstream stimuli exploit RIP kinases to activate necrosis are still relatively poorly described.In the present study, we show that both IFN-γ and IFN-α/β t...

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Section: Discussionmentioning

confidence: 99%

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

Thapa

Nogusa

Chen

et al. 2013

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

307

261

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“…28 We cannot exclude the possibility of immune system activation by the primary and secondary structures of mRNA via TLR3, TLR7 and TLR8 Toll-like receptors of DCs. [40][41][42][43][44][45][46] Similar contribution from MART1 mRNA lipopolyplexes could be explored using gene-deficient mice. In our system, the effect of MART1 mRNA immunization was much higher than of MART1 DNA immunization because DNA transfection of APC requires the plasmid import in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

et al. 2007

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Immunization with mRNA encoding tumor antigen is an emerging vaccine strategy for cancer. In this paper, we demonstrate that mice receiving systemic injections of MART1 mRNA histidylated lipopolyplexes were specifically and significantly protected against B16F10 melanoma tumor progression. The originality of this work concerns the use of a new tumor antigen mRNA formulation as vaccine, which allows an efficient protection against the growth of a highly aggressive tumor model after its delivery by intravenous route. Synthetic melanoma-associated antigen MART1 mRNA was formulated with a polyethylene glycol (PEG)ylated derivative of histidylated polylysine and L-histidine-(N,N-di-n-hexadecylamine)ethylamide liposomes (termed histidylated lipopolyplexes). Lipopolyplexes comprised mRNA/polymer complexes encapsulated by liposomes. The tumor protective effect was induced with MART1 mRNA carrying a poly(A) tail length of 100 adenosines at an optimal dose of 12.5 mg per mouse. MART1 mRNA lipopolyplexes elicited a cellular immune response characterized by the production of interferon-g and the induction of cytotoxic T lymphocytes. Finally, the anti-B16 response was enhanced using a formulation containing both MART1 mRNA and MART1-LAMP1 mRNA encoding the antigen targeted to the major histocompatibility complex class II compartments by the lysosomal sorting signal of LAMP1 protein. Our results provide a basis for the development of mRNA histidylated lipopolyplexes for cancer vaccine.

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“…Activation of PKR by TPT1/TCTP mRNA. As described for viral double stranded (ds) RNAs [27,28], the mRNA for TCTP activates protein kinase R (PKR) [22], which is also the case for other mRNAs such as mRNA tropomyosin, mRNA troponin, and mRNA cardiac actin [31]. By adopting a highly structured conformation, TPT1/TCTP and other cellular mRNAs activate PKR [27].…”

Section: Tpt1/tctp Protein Pkrmentioning

confidence: 98%

“…This virus-directed response constitutes only a facet of a much wider cellular program, because it is known that some cellular RNAs and endoplasmic reticulum stress can also activate PKR [29][30][31][32][33][34][35]. It was reported that the 3 0 UTRs of the mRNAs of tropomyosin, troponin and, cardiac actin bind and activate PKR [29][30][31]. In the case of TPT1/TCTP, although the secondary structures involved have yet to be precisely mapped, both the 5 0 and the 3 0 UTR might assume ds configurations able to bind/activate PKR [22].…”

Section: Trends In Cell Biologymentioning

confidence: 99%

TPT1/ TCTP-regulated pathways in phenotypic reprogramming

Amson

Pece

Marine

et al. 2013

Trends in Cell Biology

106

112

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The 3'-untranslated regions of cytoskeletal muscle mRNAs inhibit translation by activating the double-stranded RNA-dependent protein kinase PKR

Cited by 44 publications

References 44 publications

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

TPT1/ TCTP-regulated pathways in phenotypic reprogramming

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