RNase L Induces Autophagy via c-Jun N-terminal Kinase and Double-stranded RNA-dependent Protein Kinase Signaling Pathways

Siddiqui, Mohammad Adnan; Malathi, Krishnamurthy

doi:10.1074/jbc.m112.399964

Cited by 55 publications

(74 citation statements)

References 66 publications

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“…The context of the infected cell provides multiple potential sources of signals for autophagy induction. For example, protein kinase R (PKR) and RNase L, which are activated by dsRNA, a pathogen-associated molecular pattern characteristic of viruses such as EHDV, were implicated in the induction of autophagy (23,49,50). Indeed, the infection-dependent phosphorylation of the translation regulator eIF2␣ (Fig.…”

Section: Discussionmentioning

confidence: 99%

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Shai

Schmukler

Yaniv

et al. 2013

J Virol

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The mode and timing of virally induced cell death hold the potential of regulating viral yield, viral transmission, and the severity of virally induced disease. Orbiviruses such as the epizootic hemorrhagic disease virus (EHDV) are nonenveloped and cytolytic. To date, the death of cells infected with EHDV, the signal transduction pathways involved in this process, and the consequence of their inhibition have yet to be characterized. Here, we report that the Ibaraki strain of EHDV2 (EHDV2-IBA) induces apoptosis, autophagy, a decrease in cellular protein synthesis, the activation of c-Jun N-terminal kinase (JNK), and the phosphorylation of the JNK substrate c-Jun. The production of infectious virions decreased upon inhibition of apoptosis with the pan-caspase inhibitor Q-VD-OPH (quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone), upon inhibition of autophagy with 3-methyladenine or via the knockout of the autophagy regulator Atg5, or upon treatment of infected cells with the JNK inhibitor SP600125 or the cyclin-dependent kinase (CDK) inhibitor roscovitine, which also inhibited c-Jun phosphorylation. Moreover, Q-VD-OPH, SP600125, and roscovitine partially reduced EHDV2-IBA-induced cell death, and roscovitine diminished the induction of autophagy by EHDV2-IBA. Taken together, our results imply that EHDV induces and benefits from the activation of signaling pathways involved in cell stress and death.T he epizootic hemorrhagic disease virus (EHDV) is an arbovirus (genus orbiviruses) of the Reoviridae family that is transmitted by biting midges and infects ruminants. In recent years, outbreaks of epizootic hemorrhagic disease in cattle have been reported in Israel and Turkey (1, 2), suggesting that EHDV is an emerging threat to the cattle industry in Europe (3). EHDV presents structural and sequence similarities to the better-studied bluetongue virus (BTV), sharing its repertoire of infection targets and symptoms of disease (3, 4). However, in spite of structural similarities between these viruses, a recent study suggests that preexisting immunity to BTV does not protect against EHDV infection (5). The EHDV genome is organized in 10 double-stranded RNA (dsRNA) segments encoding seven structural proteins (VP1 to VP7) and the nonstructural (NS) proteins NS1 to NS3. Recently, an additional nonstructural protein, NS4, has been identified in BTV (6, 7), raising the possibility that the same protein occurs in EHDV. The present study mainly employs the Ibaraki strain of EHDV2 (EHDV2-IBA), originally isolated from infected cattle in 1959, in Ibaraki, Japan (8). Selected experiments were also carried out with EHDV7-Israel (EHDV7-ISR), isolated from infected cattle in 2006 in Israel (1).For different types of reoviruses, including BTV, apoptosis is integral to the cellular pathogenesis they induce (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Yet the molecular mechanisms that govern reovirus-mediated induction of apoptosis are a contentious matter (10,17,19,20). For orbiviruses in general and EHDV in partic...

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Section: Discussionmentioning

confidence: 99%

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Shai

Schmukler

Yaniv

et al. 2013

J Virol

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“…It is likely that small differences in cell culture conditions and starvation conditions may contribute to discrepancies between our analysis (Figure 2) and previously published reports of the role of MAPK8/9 in MEFs [5]. The use of the small molecule SP600125, that inhibits MAPK8/9 and many other protein kinases [52], to draw conclusions concerning the specific role of MAPK8/9 may also contribute to conclusions [8,10,12–19,22,51] that contrast with those drawn from our analysis of MAPK8/9 knockout cells. Finally, some studies that have identified a role for MAPK8/9 do not focus on starvation-induced autophagy.…”

Section: Discussionmentioning

confidence: 67%

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

et al. 2018

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Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more complex than previously considered.Abbreviations: AKT: thymoma viral proto-oncogene;ALB: albumin; ATG4: autophagy related 4; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine diphosphate; DMEM: Dulbecco’s modified Eagle’s medium; EDTA: ethylenediaminetetraacetic acid; EBSS: Earle’s balanced salt solution; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HRAS: Harvey rat sarcoma virus oncogene; IgG: Immunoglobulin G; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK1: mitogen-activated protein kinase 8; MAPK9/JNK2: mitogen-activated protein kinase 9; MAPK10/JNK3: mitogen-activated protein kinase 10; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70: ribosomal protein S6 kinase, polypeptide 1; PPARA: peroxisome proliferator activated receptor alpha; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; TRP53: transforming related protein 53; TUBA: tubulin alpha; UV: ultraviolet; WT: wild-type

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“…Knock-down of endogenous proteins was determined by western blotting. Transfection of 2–5A (10 μM) was performed using lipofectamine 2000 (Invitrogen, Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s protocol as described previously [75]. Briefly, cells were plated 1 day before transfection, so that the cells are 80%–90% confluent at the time of transfection.…”

Section: Methodsmentioning

confidence: 99%

“…2–5A was diluted into serum-free media and then mixed with lipofectamine 2000 reagent for 15 min before being added to cells in growth media. Preparation of 2–5A using ATP and recombinant 2–5A synthetase (a generous gift from Rune Hartmann, University of Aarhus, Aarhus, Denmark) has been described previously [75]. PolyI:C (2 μg/mL) was transfected into cells using Polyjet reagent (SignaGen Laboratories, Gaithersburg, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…PolyI:C (2 μg/mL) was transfected into cells using Polyjet reagent (SignaGen Laboratories, Gaithersburg, MD, USA). Activity of RNase L in intact cells was determined in HeLa cells reconstituted with Flag-RNase L mutant constructs as described previously [75]. In experiments involving inhibitors, cells were preincubated with inhibitor for 1 h prior to treatment and then replaced with growth medium.…”

Section: Methodsmentioning

confidence: 99%

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RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

Dayal

Zhou

Manivannan

et al. 2017

IJMS

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The interferon antiviral pathways and prostate cancer genetics converge on a regulated endoribonuclease, RNase L. Positional cloning and linkage studies mapped Hereditary Prostate Cancer 1 (HPC1) to RNASEL. To date, there is no correlation of viral infections with prostate cancer, suggesting that RNase L may play additional roles in tumor suppression. Here, we demonstrate a role of RNase L as a suppressor of androgen receptor (AR) signaling, cell migration and matrix metalloproteinase activity. Using RNase L mutants, we show that its nucleolytic activity is dispensable for both AR signaling and migration. The most prevalent HPC1-associated mutations in RNase L, R462Q and E265X, enhance AR signaling and cell migration. RNase L negatively regulates cell migration and attachment on various extracellular matrices. We demonstrate that RNase L knockdown cells promote increased cell surface expression of integrin β1 which activates Focal Adhesion Kinase-Sarcoma (FAK-Src) pathway and Ras-related C3 botulinum toxin substrate 1-guanosine triphosphatase (Rac1-GTPase) activity to increase cell migration. Activity of matrix metalloproteinase (MMP)-2 and -9 is significantly increased in cells where RNase L levels are ablated. We show that mutations in RNase L found in HPC patients may promote prostate cancer by increasing expression of AR-responsive genes and cell motility and identify novel roles of RNase L as a prostate cancer susceptibility gene.

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RNase L Induces Autophagy via c-Jun N-terminal Kinase and Double-stranded RNA-dependent Protein Kinase Signaling Pathways

Cited by 55 publications

References 66 publications

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

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RNase L Induces Autophagy via c-Jun N-terminal Kinase and Double-stranded RNA-dependent Protein Kinase Signaling Pathways

Cited by 55 publications

References 66 publications

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

Role of the MAPK/cJun NH 2 -terminal kinase signaling pathway in starvation-induced autophagy

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

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Role of the MAPK/cJun NH ₂ -terminal kinase signaling pathway in starvation-induced autophagy