Regulation of Actin Dynamics by Protein Kinase R Control of Gelsolin Enforces Basal Innate Immune Defense

Irving, Aaron T.; Wang, Die; Vasilevski, Oliver; Latchoumanin, Olivier; Kozer, Noga; Clayton, Andrew H. A.; Szczepny, Anette; Morimoto, Hiroyuki; Xu, Dakang; Williams, Bryan R.G.; Sadler, Anthony John

doi:10.1016/j.immuni.2012.02.020

Cited by 50 publications

(51 citation statements)

References 39 publications

(39 reference statements)

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“…Also in agreement with He et al [5], we did not observe PKR dependence for all stimuli that activate the inflammasome and propose that this is, at least in part, due to indirect effects of PKR on the cell [17]. Effects of PKR on the cell cytoskeleton mean that the uptake of some stimuli is not equivalent between wild-type and PKR-ablated cells, and this activation of the inflammasomes is not equivalent.…”

Section: Discussionsupporting

confidence: 91%

“…Peritoneal macrophages were treated with lipopolysaccharide (LPS) to activate PKR [7,16] and prime the inflammasome. Because different stimuli that trigger the cryopyrin inflammasome are taken up by cells through distinct mechanisms with differing dependence on the actin cytoskeleton, which is modulated by PKR [17], we used the ionophore nigericin to minimize this potential source of variance [18]. Measures of IL-1β and IL-18 by ELISA demonstrated elevated levels of these cytokines in the supernatant from macrophages isolated (C) Quantitation of PKR kinase activity by detecting eIF2α phosphorylation and PKR autophosphorylation in fibroblasts isolated from the WT and transgenic mice (eif2ak2 −/− and eIF2αk2 tm1Lri ) treated with JetPRIME and polyI:C (3 µg/ml) for 2 h. Whole-cell lysates were probed with anti-pS 51 -eIF2α and -eIF2 antibodies (n = 3).…”

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

confidence: 99%

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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: Discussionsupporting

confidence: 91%

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

confidence: 99%

The kinase activity of PKR represses inflammasome activity

Yim

Wang

et al. 2016

Cell Res

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“…The signal transmitting mechanism is affected by the presence of β-actin. Also, the receptor signal absorption was also affected by actin cytoskeleton bundle (Irving et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

The application of pigment-protein fraction from Nannochloropsis oculata on β-actin response of Cromileptes altivelis infected with viral nervous necrosis

Yanuhar¹,

Khumaidi²

2017

Jurnal Akuakultur Indonesia

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ABSTRACTβ-actin is a prominent protein in the immune system. An outcome from gene transcription, the protein protects against pathogen infection, such as receptor clustering, antigen internalization, and regulating vesicle for antigen processing. ß -actin expression will determine the success of immune response of the organism. This study aimed to understand the role of pigment-protein fraction (PPF) from Nannochloropsis oculata in the increase of β-actin expression in humpback grouper Cromileptes altivelis infected by viral nervous necrosis (VNN). The experiment was performed with one negative control (A: normal fish) and three PPF treatments (B: fish + PPF, C: fish + VNN, and D: fish + PPF + VNN). PPF was applied through the sonde method and analyzed with immunohistochemistry technique and Immunoratio software. The results showed that PPF was able to increase β-actin expression on all treatments: A (34.9%), B (38.1%), C (39.1%), and D (51.6%). It demonstrated PPF ability to induce the increase of β-actin expression indicating an improved defense of humpback grouper C. altivelis against VNN infection.Keywords: β-actin, pigment-protein fraction, Nannochloropsis oculata, VNN ABSTRAK β-aktin adalah protein yang berfungsi penting sebagai salah satu sistem pertahanan tubuh. Protein ini merupakan hasil transkripsi dari gen yang memiliki fungsi penting dalam sistem pertahanan tubuh terhadap infeksi patogen, seperti kelompok reseptor, internalisasi antigen, dan mengatur keluar masuknya vesikel untuk pemrosesan antigen. Ekpresi β-aktin menjadi penentu berhasil atau tidaknya respons imun pada tubuh organisme. Penelitian ini bertujuan untuk mengetahui peran fraksi protein pigment (FPP) dari Nannochloropsis oculata dalam meningkatkan respons β-aktin pada ikan kerapu tikus Cromileptes altivelis yang terinfeksi viral nervous necrosis (VNN). Pengamatan dilakukan pada empat percobaan yaitu, satu kontrol (A : ikan normal) dan tiga perlakuan FPP (B : ikan + FPP, C: ikan + VNN, dan D: ikan + VNN + FPP). Pemberian FPP menggunakan metode stoned dan analisis hasil penelitian menggunakan teknik imunohistokimia dan Immunoratio. Hasil penelitian ini menunjukkan bahwa pengiduksian FPP mampu meningkatkan ekpresi β-aktin yaitu A (34,9%), B (38,1%), C (39,1%), dan D (51,6%). Hal tersebut menunjukan FPP mampu menjadi inducer yang baik untuk peningkatan ekpresi β-aktin. Meningkatnya ekspresi β-aktin bisa dijadikan sebagai indikator pertahanan tubuh ikan kerapu tikus C. altivelis terhadap infeksi VNN.Kata kunci: β-aktin, fraksi protein pigmen, Nannochloropsis oculata, VNN

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“…4C). Inhibition of expression of another DBN1 interacting protein gelsolin (GSN), previously shown to be antiviral through regulation of actin dynamics (29), had minimal effect either in WT or DBN1 −/− cells (Fig. 4 B and C).…”

Section: Dbn1 Negatively Regulates the Endocytosis Of Dynamin-dependentmentioning

confidence: 96%

Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis

Ding

Feng

et al. 2017

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

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Despite the wide administration of several effective vaccines, rotavirus (RV) remains the single most important etiological agent of severe diarrhea in infants and young children worldwide, with an annual mortality of over 200,000 people. RV attachment and internalization into target cells is mediated by its outer capsid protein VP4. To better understand the molecular details of RV entry, we performed tandem affinity purification coupled with highresolution mass spectrometry to map the host proteins that interact with VP4. We identified an actin-binding protein, drebrin (DBN1), that coprecipitates and colocalizes with VP4 during RV infection. Importantly, blocking DBN1 function by siRNA silencing, CRISPR knockout (KO), or chemical inhibition significantly increased host cell susceptibility to RV infection. Dbn1 KO mice exhibited higher incidence of diarrhea and more viral antigen shedding in their stool samples compared with the wild-type littermates. In addition, we found that uptake of other dynamin-dependent cargos, including transferrin, cholera toxin, and multiple viruses, was also enhanced in DBN1-deficient cells. Inhibition of cortactin or dynamin-2 abrogated the increased virus entry observed in DBN1-deficient cells, suggesting that DBN1 suppresses dynamin-mediated endocytosis via interaction with cortactin. Our study unveiled an unexpected role of DBN1 in restricting the entry of RV and other viruses into host cells and more broadly to function as a crucial negative regulator of diverse dynamin-dependent endocytic pathways.drebrin | rotavirus | endocytosis

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Regulation of Actin Dynamics by Protein Kinase R Control of Gelsolin Enforces Basal Innate Immune Defense

Cited by 50 publications

References 39 publications

The kinase activity of PKR represses inflammasome activity

The kinase activity of PKR represses inflammasome activity

The application of pigment-protein fraction from Nannochloropsis oculata on β-actin response of Cromileptes altivelis infected with viral nervous necrosis

Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis

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