Regulation of Protein Kinase R by Epstein-Barr Virus EBER1 RNA

Zerbe, Cassie; Cole, James L.

doi:10.1021/acs.biochem.0c00088

Cited by 7 publications

(7 citation statements)

References 74 publications

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“… 15 Similarly, adenovirus VAI RNA produces KD dimers but does not activate PKR. 16 Finally, inactivating mutations within the PKR dimer interface that disrupt key electrostatic and hydrogen-binding interactions fail to abolish KD dimerization. 15 Together, these observations demonstrate that dimerization is a necessary but not sufficient step for the activation of PKR and point to the existence of one or more inactive dimer configurations.…”

Section: Discussionmentioning

confidence: 99%

“…We have identified several RNAs that can bind two PKR monomers and induce kinase domain dimerization but nonetheless fail to activate. 15 , 16 Affinity cleavage measurements suggested that simultaneous binding of both dsRBDs occurs only on activating RNAs. 17 NMR data indicate that only the N-terminus of dsRBD2 interacts with a short, nonactivating dsRNA, but extensive interactions with dsRBD2 occur upon binding to a longer, activating sequence.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of dsRBD2 to PKR Activation

et al. 2021

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Protein kinase R (PKR) is a key pattern recognition receptor of the innate immune pathway. PKR is activated by double-stranded RNA (dsRNA) that is often produced during viral genome replication and transcription. PKR contains two tandem double-stranded RNA binding domains at the N-terminus, dsRBD1 and dsRBD2, and a C-terminal kinase domain. In the canonical model for activation, RNAs that bind multiple PKRs induce dimerization of the kinase domain that promotes an active conformation. However, there is evidence that dimerization of the kinase domain is not sufficient to mediate activation and PKR activation is modulated by the RNA-binding mode. dsRBD2 lacks most of the consensus RNA-binding residues, and it has been suggested to function as a modulator of PKR activation. Here, we demonstrate that dsRBD2 regulates PKR activation and identify the N-terminal helix as a critical region for modulating kinase activity. Mutations in dsRBD2 that have minor effects on overall dsRNA-binding affinity strongly inhibit the activation of PKR by dsRNA. These mutations also inhibit RNA-independent PKR activation. These data support a model where dsRBD2 has evolved to function as a regulator of the kinase.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contribution of dsRBD2 to PKR Activation

et al. 2021

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“…Moreover, recently it has been found that, upon stimulation in vitro, the Epstein-Barr virus (EBV)infected IgA+ B cells secreted Gd-IgA1 and that B cells and their IgA+ subpopulation in PBMCs of IgAN patients displayed a significantly higher frequency of EBV infection than did cells of the same phenotype from non-IgAN patients (39). Interestingly, a different study very recently showed that PKR is regulated by EBV RNA (40).…”

Section: Creb Activation By Phosphorilation Leads To Il-6 Incerase In...mentioning

confidence: 99%

“…Bacterial and viral RNA may effectively further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production.Moreover, recently has been found that, upon stimulation in vitro, the Epstein-Barr virus (EBV)infected IgA+ B cells secreted Gd-IgA1 and that B cells and their IgA+ subpopulation in PBMCs of IgAN patients displayed a significantly higher frequency of EBV infection than did cells of the same phenotype from non-IgAN patients(39). Interestingly, a different study very recently showed that PKR is regulated by EBV RNA(40). This kind of mechanism, driven by the epigenetic silencing of VTRNA2-1, may therefore explain both the high levels of IL-6, and infection involvement in the disease, and recent data showingmicrobiota involvment in IgAN (9) (41) (42).…”

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confidence: 99%

Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

Sallustio

Picerno

Cimmarusti

et al. 2022

Preprint

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Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy. Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients. Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation. Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN. Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs. The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin. In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients.

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“…Notably, disruption of the essential central domain pseudoknot structure converts VA RNAI from an inhibitor into an efficient PKR activator [ 45 ]. Taken together, it is likely that a specific structural conformation of the VA RNAI-PKR complex rather than physical sequestering of PKR by VA RNAI is needed for PKR inhibition [ 12 , 45 , 46 , 65 ].…”

Section: Va Rnamentioning

confidence: 99%

Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs

Punga

Darweesh

Akusjärvi

2020

Viruses

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Human adenoviruses (HAdVs) are common pathogens causing a variety of respiratory, ocular and gastrointestinal diseases. To accomplish their efficient replication, HAdVs take an advantage of viral small non-coding RNAs (sncRNAs), which have multiple roles during the virus lifecycle. Three of the best-characterized HAdV sncRNAs; VA RNA, mivaRNA and MLP-TSS-sRNA will be discussed in the present review. Even though VA RNA has been extensively characterized during the last 60 years, this multifunctional molecule continues to surprise us as more of its structural secrets unfold. Likely, the recent developments on mivaRNA and MLP-TSS-sRNA synthesis and function highlight the importance of these sncRNA in virus replication. Collectively, we will summarize the old and new knowledge about these three viral sncRNAs with focus on their synthesis, structure and functions.

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Regulation of Protein Kinase R by Epstein-Barr Virus EBER1 RNA

Cited by 7 publications

References 74 publications

Contribution of dsRBD2 to PKR Activation

Contribution of dsRBD2 to PKR Activation

Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs

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