RGD Reference Report - ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. - Rat Genome Database

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ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells.

Authors: Tan, Zhongyuan  Zhang, Wanpo  Sun, Jianhong  Fu, Zuquan  Ke, Xianliang  Zheng, Caishang  Zhang, Yuan  Li, Penghui  Liu, Yan  Hu, Qinxue  Wang, Hanzhong  Zheng, Zhenhua 
Citation: Tan Z, etal., J Neuroinflammation. 2018 Sep 21;15(1):275. doi: 10.1186/s12974-018-1311-5.
RGD ID: 32733625
Pubmed: PMID:30241539   (View Abstract at PubMed)
PMCID: PMC6151056   (View Article at PubMed Central)
DOI: DOI:10.1186/s12974-018-1311-5   (Journal Full-text)


BACKGROUND: Many viruses depend on the extensive membranous network of the endoplasmic reticulum (ER) for their translation, replication, and packaging. Certain membrane modifications of the ER can be a trigger for ER stress, as well as the accumulation of viral protein in the ER by viral infection. Then, unfolded protein response (UPR) is activated to alleviate the stress. Zika virus (ZIKV) is a mosquito-borne flavivirus and its infection causes microcephaly in newborns and serious neurological complications in adults. Here, we investigated ER stress and the regulating model of UPR in ZIKV-infected neural cells in vitro and in vivo.
METHODS: Mice deficient in type I and II IFN receptors were infected with ZIKV via intraperitoneal injection and the nervous tissues of the mice were assayed at 5 days post-infection. The expression of phospho-IRE1, XBP1, and ATF6 which were the key markers of ER stress were analyzed by immunohistochemistry assay in vivo. Additionally, the nuclear localization of XBP1s and ATF6n were analyzed by immunohistofluorescence. Furthermore, two representative neural cells, neuroblastoma cell line (SK-N-SH) and astrocytoma cell line (CCF-STTG1), were selected to verify the ER stress in vitro. The expression of BIP, phospho-elF2α, phospho-IRE1, and ATF6 were analyzed through western blot and the nuclear localization of XBP1s was performed by confocal immunofluorescence microscopy. RT-qPCR was also used to quantify the mRNA level of the UPR downstream genes in vitro and in vivo.
RESULTS: ZIKV infection significantly upregulated the expression of ER stress markers in vitro and in vivo. Phospho-IRE1 and XBP1 expression significantly increased in the cerebellum and mesocephalon, while ATF6 expression significantly increased in the mesocephalon. ATF6n and XBP1s were translocated into the cell nucleus. The levels of BIP, ATF6, phospho-elf2α, and spliced xbp1 also significantly increased in vitro. Furthermore, the downstream genes of UPR were detected to investigate the regulating model of the UPR during ZIKV infection in vitro and in vivo. The transcriptional levels of atf4, gadd34, chop, and edem-1 in vivo and that of gadd34 and chop in vitro significantly increased.
CONCLUSION: Findings in this study demonstrated that ZIKV infection activates ER stress in neural cells. The results offer clues to further study the mechanism of neuropathogenesis caused by ZIKV infection.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Zika fever  ISOAtf4 (Mus musculus)32733625; 32733625mRNA:increased expression:brainRGD 
Zika fever  IEP 32733625; 32733625; 32733625; 32733625mRNA:increased expression:brainRGD 
Zika fever  ISODdit3 (Mus musculus)32733625; 32733625mRNA:increased expression:brainRGD 
Zika fever  ISOEdem1 (Mus musculus)32733625; 32733625mRNA:increased expression:brainRGD 
Zika fever  ISOErn1 (Mus musculus)32733625; 32733625 RGD 
Zika fever  IEP 32733625 RGD 
Zika fever  ISOHspa5 (Mus musculus)32733625; 32733625mRNA and protein:increased expression:brainRGD 
Zika fever  IEP 32733625mRNA and protein:increased expression:brainRGD 
Zika fever  ISOPpp1r15a (Mus musculus)32733625; 32733625mRNA:increased expression:brainRGD 
Zika fever  ISOXbp1 (Mus musculus)32733625; 32733625protein:increased expression:cerebellum and mesocephalonRGD 
Zika fever  IEP 32733625protein:increased expression:cerebellum and mesocephalonRGD 

Objects Annotated

Genes (Rattus norvegicus)
Atf4  (activating transcription factor 4)
Ddit3  (DNA-damage inducible transcript 3)
Edem1  (ER degradation enhancing alpha-mannosidase like protein 1)
Ern1  (endoplasmic reticulum to nucleus signaling 1)
Hspa5  (heat shock protein family A (Hsp70) member 5)
Ppp1r15a  (protein phosphatase 1, regulatory subunit 15A)
Xbp1  (X-box binding protein 1)

Genes (Mus musculus)
Atf4  (activating transcription factor 4)
Ddit3  (DNA-damage inducible transcript 3)
Edem1  (ER degradation enhancer, mannosidase alpha-like 1)
Ern1  (endoplasmic reticulum to nucleus signalling 1)
Hspa5  (heat shock protein 5)
Ppp1r15a  (protein phosphatase 1, regulatory subunit 15A)
Xbp1  (X-box binding protein 1)

Genes (Homo sapiens)
ATF4  (activating transcription factor 4)
DDIT3  (DNA damage inducible transcript 3)
EDEM1  (ER degradation enhancing alpha-mannosidase like protein 1)
ERN1  (endoplasmic reticulum to nucleus signaling 1)
HSPA5  (heat shock protein family A (Hsp70) member 5)
PPP1R15A  (protein phosphatase 1 regulatory subunit 15A)
XBP1  (X-box binding protein 1)


Additional Information