XBP1-Mediated BiP/GRP78 Upregulation Copes with Oxidative Stress in Mosquito Cells during Dengue 2 Virus Infection

Chen, Tien-Huang; Chiang, Yi‐Hsuan; Hou, Jiun-Nan; Cheng, Chih-Chieh; Sofiyatun, Eny; Chiu, Cheng-Hsun; Chen, Wei-June

doi:10.1155/2017/3519158

Cited by 25 publications

(18 citation statements)

References 57 publications

(81 reference statements)

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“…2000 ). Previous studies have demonstrated that during DENV infection the concentration of calcium ions rises in the cytoplasm ( Chen et al. 2017 ) as levels are simultaneously depleted in the ER ( Dionicio et al.…”

Section: Discussionmentioning

confidence: 99%

The transcriptional response of Aedes aegypti with variable extrinsic incubation periods for dengue virus

Koh

Allen

Herbert

et al. 2018

Genome Biology and Evolution

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Dengue fever is the most prevalent arboviral disease globally. Dengue virus is transmitted primarily by the Aedes aegypti mosquito. One measure of the mosquito’s efficiency as a vector is the extrinsic incubation period (EIP), which is the time between the ingestion of viremic blood and the emergence of virions in the saliva. The longer it takes virus to infect the midgut and traverse to the saliva, the fewer opportunities the mosquito will have to transmit the pathogen over its lifetime. We have shown previously that EIP for dengue virus is highly heritable and that it is negatively correlated with vector lifespan. Here, we examined the transcriptional profiles for mosquitoes that varied in their EIP phenotype and identified pathways associated with either short or long EIP. We found that mosquitoes with short EIP have less active immune responses but higher levels of protein translation and calcium ion homeostasis and that mosquitoes with longer EIP may have slower metabolism. These findings indicate a complex interplay between calcium ion distribution, ribosome biogenesis, and metabolism and reveal potential pathways that could be modified to slow the rate of viral progression and hence limit lifetime transmission capability.

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Section: Discussionmentioning

confidence: 99%

The transcriptional response of Aedes aegypti with variable extrinsic incubation periods for dengue virus

Koh

Allen

Herbert

et al. 2018

Genome Biology and Evolution

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“…The UPR as mentioned above is caused by the accumulation of unfolded or misfolded proteins in the ER; which actually resulted in changes in X-box binding protein 1 (XBP1) and splicing activity [ 41 ]. The UPR generally leads to activation of three signaling pathways including PERK, IRE1 and ATF6 [ 5 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication

Hou

Chen

Chiang

et al. 2017

Viruses

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Survival of mosquitoes from dengue virus (DENV) infection is a prerequisite of viral transmission to the host. This study aimed to see how mosquito cells can survive the infection during prosperous replication of the virus. In C6/36 cells, global protein translation was shut down after infection by DENV type 2 (DENV2). However, it returned to a normal level when infected cells were treated with an inhibitor of the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway. Based on a 7-Methylguanosine 5′-triphosphate (m7GTP) pull-down assay, the eukaryotic translation initiation factor 4F (eIF4F) complex was also identified in DENV2-infected cells. This suggests that most mosquito proteins are synthesized via canonical cap-dependent translation. When the PERK signal pathway was inhibited, both accumulation of reactive oxygen species and changes in the mitochondrial membrane potential increased. This suggested that ER stress response was alleviated through the PERK-mediated shutdown of global proteins in DENV2-infected C6/36 cells. In the meantime, the activities of caspases-9 and -3 and the apoptosis-related cell death rate increased in C6/36 cells with PERK inhibition. This reflected that the PERK-signaling pathway is involved in determining cell survival, presumably by reducing DENV2-induced ER stress. Looking at the PERK downstream target, α-subunit of eukaryotic initiation factor 2 (eIF2α), an increased phosphorylation status was only shown in infected C6/36 cells. This indicated that recruitment of ribosome binding to the mRNA 5′-cap structure could have been impaired in cap-dependent translation. It turned out that shutdown of cellular protein translation resulted in a pro-survival effect on mosquito cells in response to DENV2 infection. As synthesis of viral proteins was not affected by the PERK signal pathway, an alternate mode other than cap-dependent translation may be utilized. This finding provides insights into elucidating how the PERK signal pathway modulates dynamic translation of proteins and helps mosquito cells survive continuous replication of the DENV2. It was ecologically important for virus amplification in mosquitoes and transmission to humans.

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“…However, this contrasts with most other viral infections, which induce the upregulation of GRP78. [53][54][55] Recent studies have shown that some viruses manipulate the host UPR to maintain an environment favorable for persistent infection. For example, hepatitis C virus and cytomegalovirus have been reported to suppress the IRE1-XBP1 pathway of the UPR, 56,57 which was assumed to contribute to persistent infection of the virus in the cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1–infected cells

et al. 2020

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Patients with adult T-cell leukemia (ATL) exhibit a poor prognosis and overall survival rate when treated with standard chemotherapy, highlighting the continued requirement for the development of novel safe and effective therapies for human T-cell leukemia virus type 1 (HTLV-1)-related diseases. In this study, we demonstrated that MK-2048, a second-generation HIV-1 integrase (IN) inhibitor, potently and selectively kills HTLV-1–infected cells. Differential transcriptome profiling revealed significantly elevated levels of gene expression of the unfolded protein response (UPR) PKR-like ER kinase (PERK) signaling pathway in ATL cell lines following MK-2048 treatment. We also identified a significant downregulation in glucose regulated protein 78 (GRP78), a master regulator of the UPR in the CD4+CADM1+ HTLV-1–infected cell population of primary HTLV-1 carrier peripheral blood mononuclear cells (PBMCs) (n = 9), suggesting that HTLV-1–infected cells are hypersensitive to endoplasmic reticulum (ER) stress-mediated apoptosis. MK-2048 efficiently reduced proviral loads in primary HTLV-1 carrier PBMCs (n = 4), but had no effect on the total numbers of these cells, indicating that MK-2048 does not affect the proliferation of HTLV-1–uninfected PBMCs. MK-2048 specifically activated the ER stress–related proapoptotic gene, DNA damage-inducible transcript 3 protein (DDIT3), also known as C/EBP homologous protein (CHOP), in HTLV-1–infected but not uninfected cells of HTLV-1–carrier PBMCs. Our findings demonstrated that MK-2048 selectively induces HTLV-1–infected cell apoptosis via the activation of the UPR. This novel regulatory mechanism of the HIV IN inhibitor MK-2048 in HTLV-1–infected cells provides a promising prophylactic and therapeutic target for HTLV-1–related diseases including ATL.

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XBP1-Mediated BiP/GRP78 Upregulation Copes with Oxidative Stress in Mosquito Cells during Dengue 2 Virus Infection

Cited by 25 publications

References 57 publications

The transcriptional response of Aedes aegypti with variable extrinsic incubation periods for dengue virus

The transcriptional response of Aedes aegypti with variable extrinsic incubation periods for dengue virus

PERK Signal-Modulated Protein Translation Promotes the Survivability of Dengue 2 Virus-Infected Mosquito Cells and Extends Viral Replication

Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1–infected cells

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