Viral Regulation of RNA Granules in Infected Cells

Zhang, Qiang; Sharma, Nisha; Zheng, Zhi-Ming; Chen, Mingzhou

doi:10.1007/s12250-019-00122-3

Cited by 64 publications

(94 citation statements)

References 165 publications

(254 reference statements)

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“…After viral infection, PKR binds to viral double-stranded RNA (dsRNA), which activates the autophosphorylation of the kinase. Activation of PKR phosphorylates eIF2α (15)(16)(17)(18), inhibits the formation of the ternary complex tRNAiMet-GTP-eIF2, and initiates assembly of SGs, thereby preventing cell translation (9,16,17,19). For example, RSV-induced SGs are mediated by PKR-dependent eIF2α phosphorylation (9,20).…”

mentioning

confidence: 99%

Typical Stress Granule Proteins Interact with the 3′ Untranslated Region of Enterovirus D68 To Inhibit Viral Replication

Cheng

Gao

Zhu

et al. 2020

J Virol

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Stress granules (SGs) are formed in the cytoplasm under environmental stress, including viral infection. Human enterovirus D68 (EV-D68) is a highly pathogenic virus which can cause serious respiratory and neurological diseases. At present, there is no effective drug or vaccine against EV-D68 infection, and the relationship between EV-D68 infection and SGs is poorly understood. This study revealed the biological function of SGs in EV-D68 infection. Our results suggest that EV-D68 infection induced the accumulation of SG marker proteins Ras GTPase-activated protein-binding protein 1 (G3BP1), T cell intracellular antigen 1 (TIA1), and human antigen R (HUR) in the cytoplasm of infected host cells during early infection but inhibited their accumulation during the late stage. Simultaneously, we revealed that EV-D68 infection induces HUR, TIA1, and G3BP1 colocalization, which marks the formation of typical SGs dependent on protein kinase R (PKR) and eIF2α phosphorylation. In addition, we found that TIA1, HUR, and G3BP1 were capable of targeting the 3′ untranslated regions (UTRs) of EV-D68 RNA to inhibit viral replication. However, the formation of SGs in response to arsenite (Ars) gradually decreased as the infection progressed, and G3BP1 was cleaved in the late stage as a strategy to antagonize SGs. Our findings have important implications in understanding the mechanism of interaction between EV-D68 and the host while providing a potential target for the development of antiviral drugs. IMPORTANCE EV-D68 is a serious threat to human health, and there are currently no effective treatments or vaccines. SGs play an important role in cellular innate immunity as a target with antiviral effects. This manuscript describes the formation of SGs induced by EV-D68 early infection but inhibited during the late stage of infection. Moreover, TIA1, HUR, and G3BP1 can chelate a specific site of the 3′ UTR of EV-D68 to inhibit viral replication, and this interaction is sequence and complex dependent. However, this inhibition can be antagonized by overexpression of the minireplicon. These findings increase our understanding of EV-D68 infection and may help identify new antiviral targets that can inhibit viral replication and limit the pathogenesis of EV-D68.

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confidence: 99%

Typical Stress Granule Proteins Interact with the 3′ Untranslated Region of Enterovirus D68 To Inhibit Viral Replication

Cheng

Gao

Zhu

et al. 2020

J Virol

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“…This is consistent with previous studies showing that infection with the vaccine strain 17D induces the formation of stress granules in human dendritic cells and hamster kidney cells (53). Thus, formation of stress granules seems to be a general feature of flavivirus infection (35, 36, 54, 55). However, unlike WNV, DENV, ZIKV and the related tick-borne encephalitis virus (35, 36, 38, 54–57), YFV does not seem to efficiently antagonize stress granule biogenesis.…”

Section: Discussionmentioning

confidence: 99%

RIG-I and PKR, but not stress granules, mediate the pro-inflammatory response to Yellow fever virus

Beauclair

Streicher

Bruni

et al. 2020

Preprint

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16 17 18 19 20 21 22 23 24 25 26 42 cytokine induction in YFV-infected hepatocytes, in a stress granule-independent manner. Therefore, by 43 showing the uncoupling of the early cytokine response from the stress granules formation, our model 44 challenges the current view by which stress granules are required for the mounting of the acute antiviral 45 response. 46 47 48 in human hepatocytes infected with YFV. We show that YFV infection promotes the formation of 54 cytoplasmic structures, termed stress granules, in a PKR-, but not RIG-I-dependent manner. Whilst stress 55 granules were previously postulated to be essential platforms for immune activation, we found that they are 56 not required for pro-inflammatory mediators' production upon YFV infection. Collectively, our work 57 uncovered molecular events triggered by the replication of YFV, which could prove instrumental in 58 clarifying the pathogenesis of the disease, with possible repercussions on disease management. 59 60 61 101 undergo a conformational change, which allows interaction with the adaptor protein MAVS and 102 subsequent recruitment of signaling complexes that comprises protein kinases such as TBK1, IKKα, 103 IKKβ and IKKε (14). These events lead to the activation and nuclear translocation of the transcription 104 factors IRF3 and NF-κB, which stimulate the rapid expression of pro-inflammatory cytokines and type 105 I interferons (IFNs). 106 RIG-I plays an important role in initiating the IFN-mediated antiviral response against DENV and 107 ZIKV (15-18). Induction of cytokines upon infection with the vaccine strain of YFV is also mediated 108 129 antiviral nature (27, 28, 30). Here, we investigated the role of RIG-I, PKR and stress granules in the 130 induction of inflammatory cytokines upon infection of hepatoma cells with YFV.

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“…Viruses have adopted several mechanisms to repress the assembly of stress granules and utilize SG protein components for viral polyprotein synthesis instead [74]. For example, herpes simplex virus genome encodes γ 1 34.5 protein that functionally mimics the activity of GADD34 and directs the dephosphorylation of eIF2α [75].…”

Section: Zikv Inhibits Cytoplasmic Stress Granules Formationmentioning

confidence: 99%

“…ZIKV utilized these SG core proteins for viral protein and virion production. Beside regulating eIF2α phosphorylation and hijacking key SG proteins, RNA viruses were reportedly capable of interfering SGs assembly through cleaving and redistributing SGs nucleating factors [74]. It was previously reported that ZIKV NS2B-NS3 protease could cleave host antiviral factors to impair intrinsic host defense; intriguingly, ZIKV did not mediate the cleavage of SG factors even though SGs assembly was affected by ZIKV NS3 and NS2B-NS3 protease [77][78][79][80][81].…”

Section: Zikv Inhibits Cytoplasmic Stress Granules Formationmentioning

confidence: 99%

Endoplasmic reticulum: a focal point of Zika virus infection

et al. 2020

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Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKVaffected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.

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Viral Regulation of RNA Granules in Infected Cells

Cited by 64 publications

References 165 publications

Typical Stress Granule Proteins Interact with the 3′ Untranslated Region of Enterovirus D68 To Inhibit Viral Replication

Typical Stress Granule Proteins Interact with the 3′ Untranslated Region of Enterovirus D68 To Inhibit Viral Replication

RIG-I and PKR, but not stress granules, mediate the pro-inflammatory response to Yellow fever virus

Endoplasmic reticulum: a focal point of Zika virus infection

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