PKR Stimulates NF-κB Irrespective of Its Kinase Function by Interacting with the IκB Kinase Complex

Bonnet, Marion; Weil, Robert; Dam, Elisabeth; Hovanessian, Ara G.; Meurs, Éliane

doi:10.1128/mcb.20.13.4532-4542.2000

Cited by 210 publications

(191 citation statements)

References 66 publications

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“…Notably, there is increased LPS-dependent induction of TNFα in the K271R-PKR cells compared with the wild-type and PKR-ablated cells ( Figure 3D). This is consistent with the previously reported kinase-independent activation of nuclear factor κB (NF-κB)-dependent cell signaling by PKR [9], and is in accordance with the elevated expression of kinase-dead PKR ( Figure 2C) [21]. In keeping with these genetic experiments, treatment of wild-type primary peritoneal macrophages with the PKR inhibitor, 2-aminopurine (2-AP), also promoted production of IL-1β as measured by ELISA ( Figure 3E).…”

Section: Pkr Represses Production Of the Inflammatory Il-1β And Il-18supporting

confidence: 82%

“…Previous reports have advanced that PKR modulates other cell signaling pathways by acting as a scaffold molecule [7,8]. This activity of PKR appears not to require kinase activity [9,10] and is at least partly mediated through an association with the tumor necrosis factor (TNF) receptor-associated factor (TRAF) adaptor molecules [11]. However, the TRAF adaptors, which have an uncertain role in inflammasome activity [12], were not implicated.…”

Section: Introductionmentioning

confidence: 96%

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The kinase activity of PKR represses inflammasome activity

Yim

Wang

et al. 2016

Cell Res

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The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR. We used this animal together with a previously generated transgenic mouse that is ablated for PKR expression to determine the role of PKR in regulating the activity of the cryopyrin inflammasome. Our data demonstrate that, in contradiction to earlier reports, PKR represses cryopyrin inflammasome activity. We demonstrate that this control is mediated through the established function of PKR to inhibit protein translation of constituents of the inflammasome to prevent initial priming during innate immune signaling. These findings identify an important role for PKR to dampen inflammation during the innate immune response and caution against the previously proposed therapeutic strategy to inhibit PKR to treat inflammation.

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Section: Pkr Represses Production Of the Inflammatory Il-1β And Il-18supporting

confidence: 82%

Section: Introductionmentioning

confidence: 96%

The kinase activity of PKR represses inflammasome activity

Yim

Wang

et al. 2016

Cell Res

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“…The IKK complex then phosphorylates IKB, the inhibitory subunit of NFkB. This event leads to IkB degradation with subsequent release and nuclear translocation of NFkB (Bonnet et al, 2000;Gil et al, , 2001Ishii et al, 2001;Offermann et al, 1995;Zamanian-Daryoush et al, 2000). It has been postulated that increasing PKR activity has a net tumor suppressive effect within the cell.…”

Section: Introductionmentioning

confidence: 99%

Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR

et al. 2002

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The interferon-inducible, double-stranded RNA (dsRNA)-activated protein kinase, PKR, plays key roles in regulation of cell growth and differentiation, and has been postulated as a tumor suppressor. Downstream effectors of PKR include the translation initiation factor, eIF2a, and the transcription factor, NF-kB. We found elevated levels of PKR protein, dsRNA-dependent PKR autophosphorylation activity, and phosphorylated eIF2a in melanoma cells compared to nontransformed melanocytes in culture. Treatment with interferon-a2b further induced PKR expression and activity. Immunohistochemical analysis of primary melanomas demonstrated minimal PKR immunoreactivity, but melanoma lymph node metastases expressed a high level of PKR protein. Furthermore, analysis of colon cancer specimens revealed that transformation from normal mucosa to adenomas and carcinomas was coincident with an increase in PKR expression. These data do not support the concept of PKR as a classic tumor suppressor but instead suggest that PKR upregulation occurs at defined steps in cancer progression, probably as a cellular response to neoplasia.

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“…25 As seen before with RIP1, 34 the catalytic activity of PKR is not required for NF-kB activation. 35 Similar to RIP1, PKR can activate NF-kB via interaction with TRAFs and the I k B kinase (IKK) complex. 27,36 Apoptosis coupled with phagocytosis is often considered as a 'clean death' preventing the release of the intracellular content of the cell.…”

Section: Discussionmentioning

confidence: 99%

“…35 S-labeled PKR and RIP1 were produced by using pCDM8-PKR and pCR3-FLAG-RIP1 vectors (1 mg) as templates for in vitro coupled transcription translation in a reticulocyte lysates system (Promega Biotech, Madison, WI, USA). Translation reaction (2 ml) was incubated for 1.5 h at 371C with 200 nM recombinant-purified caspases-8 in a total volume of 25 ml of cell-free system buffer containing 220 mM mannitol, 68 mM sucrose, 2 mM NaCl, 2.5 mM KH 2 PO 4 ,…”

Section: Discussionmentioning

confidence: 99%

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

Kalai¹,

Suin²,

Festjens³

et al. 2007

Cell Death Differ

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We have studied the involvement of receptor interacting protein kinase-1 (RIP1) and dsRNA-activated protein kinase (PKR) in external dsRNA-induced apoptotic and necrotic cell death in Jurkat T cell lymphoma. Our results suggest that RIP1 plays an imported role in dsRNA-induced apoptosis and necrosis. We demonstrated that contrary to necrosis, protein synthesis is inhibited in apoptosis. Here, we show that phosphorylation of translation initiation factor 2-a (eukaryotic initiation factor 2-a (eIF2-a)) and its kinase, PKR, occur in dsRNA-induced apoptosis but not in necrosis. These events are caspase-dependent and coincide with the appearance of the caspase-mediated PKR fragments, N-terminal domain (ND) and kinase domain (KD). Our immunoprecipitation experiments demonstrated that both fragments could independently co-precipitate with full-length PKR. Expression of PKR-KD leads to PKR and eIF2-a phosphorylation and inhibits protein translation, whereas that of PKR-ND does not. Co-expression of PKR-ND and PKR-KD promotes their interaction with PKR, PKR and eIF2-a phosphorylation and suppresses protein translation better than PKR-KD alone. Our findings suggest a caspase-dependent mode of activation of PKR in apoptosis in which the PKR-KD fragment interacts with and activates intact PKR. PKR-ND facilitates the interaction of PKR-KD with full-length PKR and thus the activation of the kinase and amplifies the translation inhibitory signal.

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PKR Stimulates NF-κB Irrespective of Its Kinase Function by Interacting with the IκB Kinase Complex

Cited by 210 publications

References 66 publications

The kinase activity of PKR represses inflammasome activity

The kinase activity of PKR represses inflammasome activity

Neoplastic progression in melanoma and colon cancer is associated with increased expression and activity of the interferon-inducible protein kinase, PKR

The caspase-generated fragments of PKR cooperate to activate full-length PKR and inhibit translation

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