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      Upregulation of CHOP participates in caspase activation and virus release in human astrovirus-infected cells.

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          Abstract

          Human astroviruses (HAstVs), non-enveloped RNA viruses with positive-sense RNA genomes, are an important cause of acute gastroenteritis in young children, although the processes that produce infectious virions are not clearly defined. To track the viral replication complex (RC) upon HAstV1 infection, the subcellular distribution of double-stranded (ds) RNA and of ORF1b, a viral RNA polymerase, was examined by immunocytochemistry. Foci that were positive for dsRNA and for ORF1b were co-localized, and both foci were also co-localized with resident proteins of the endoplasmic reticulum (ER). Focusing on the association between the HAstV RC and ER, we examined the expression of unfolded protein response (UPR) markers and found that targets of eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4), including CCAAT/enhancer-binding protein homologous protein (CHOP), a proapoptotic transcription factor, were upregulated at the late phase in HAstV-infected cells. Consistently, eIF2α was phosphorylated at the late phase of HAstV infection. The formation of foci resembling stress granules, another known downstream response to eIF2α phosphorylation, was also observed at the same period. Phosphorylation of eIF2α was attenuated in protein kinase R (PKR)-knockdown cells, suggesting that, unlike the canonical ER stress response, PKR was involved in eIF2α phosphorylation in response to HAstV infection. Studies have indicated that immature HAstV capsid protein is processed by caspases, and caspase cleavage is integral to particle release. Inhibition of CHOP upregulation reduced caspase activation and the release of HAstV RNA from cells during HAstV infection. Our results suggest that the eIF2α-ATF4-CHOP pathway participates in HAstV propagation.

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          Author and article information

          Journal
          J. Gen. Virol.
          The Journal of general virology
          Microbiology Society
          1465-2099
          0022-1317
          May 2019
          : 100
          : 5
          Affiliations
          [1 ] 1​Section of Gene Therapy, Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan.
          [2 ] 2​Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan.
          [3 ] 3​Kato Ladies Clinic, Tokyo 160-0023, Japan.
          [4 ] 4​Laboratory of Radiation Safety, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan.
          Article
          10.1099/jgv.0.001250
          30912739
          28ccfc62-261c-46ed-a973-3ee94d2214f0
          History

          unfolded protein response,eukaryotic translation initiation factor 2α (eIF2α),caspase,Astrovirus

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