Journal: PLOS Biology
Article Title: The non-vesicular cholesterol transporter GRAMD1C is a pan-coronavirus antiviral target
doi: 10.1371/journal.pbio.3003736
Figure Lengend Snippet: (A) Schematic of 20α-HC-mediated blockade of cholesterol transport by the GRAMD1C ASTER domain from PM to ER. (B) PK-15 cells were incubated with different concentrations of 20α-HC in advance for 8 hours, and then cells were infected with TGEV (MOI = 0.1). Subsequently, the viral titer assay was performed. (C) The TGEV N protein was detected by immunofluorescence assays with different concentrations of 20α-HC. Scale bar, 400 µm. (D) PK-15 cells were infected with TGEV (MOI = 0.1) and 20α-HC was added after viral entry for 8 hours. The TGEV titers were tested at 24 hpi. The TGEV N copy number was assessed by RT-qPCR assay at 24 hpi. (E) Confocal microscopy to evaluate TGEV replication by detecting dsRNA formation in cells treated with 20α-HC after virus entry. The cells were infected with TGEV (MOI = 1) for 12 hours. Scale bars, 10 µm. (F) Co-localization of TGEV-nsp3-HA (green) and TGEV-nsp4-His (red) was analyzed by confocal microscopy in HEK-293T cells with or without inhibitor treatment for 8 hours, after transfection. Scale bar, 10 μm. (G and H) TEM analysis demonstrated the presence of DMVs in WT and inhibitor-treated cells following the overexpression of plasmids encoding nsp3 and nsp4. DMVs were manually counted within complete single-cell profiles ( n = 5 cell profiles per group). Scale bar, 2 µm. (G) HEK293T cells overexpressed with nsp3 and nsp4. Atypical crescent-shaped structures in inhibitor-treated cells are denoted by red arrows. (H) PK-15 cells overexpressed with nsp3 and nsp4. (I) Caco-2 cells were infected with HCoV-229E (MOI = 0.1), and then cells were incubated with 10µM 20α-HC for 8 hours. The HCoV-229E N protein and virus titers were detected at 36 hpi. (J) Vero-E6 cells were infected with SARS-CoV-2 (MOI = 0.01), and then cells were incubated with 30µM 20α-HC for 8 hours. The SARS-CoV-2 N protein and virus titers were detected at 24 hpi. (K) Vero-E6 cells were infected with PEDV (MOI = 0.1), and then cells were incubated with 30µM 20α-HC for 8 hours. The PEDV titers were tested at 24 hpi. PK-15 cells were infected with PDCoV (MOI = 5) in the presence of 7.5 μg/ml trypsin, and then cells were incubated with 30µM 20α-HC for 8 hours. The PDCoV titers were tested at 24 hpi. L929 cells were infected with MHV (MOI = 0.01), and then cells were incubated with 30µM 20α-HC for 8 hours, The MHV titers were tested at 18 hpi. (L) The proposed model of the roles of GRAMD1C in DMV biogenesis. During the coronavirus replication stage, the viral nsp3 and nsp4 induce zippering and bending of the ER. In this process, nsp4 recruits GRAMD1C to DMV formation sites by binding to its TM domain, utilizing cholesterol delivered to the ER by GRAMD1C for DMV biogenesis. In GRAMD1C-KO cells or inhibitor-treated cells, insufficient cholesterol supply at DMV formation sites results in the generation of only crescent-shaped vesicular structures, thereby inhibiting DMV formation. The means and SDs of the results from three independent experiments are shown. ns, not significant; ** P < 0.01; *** P < 0.001; **** P < 0.0001. P -values were determined by two-tailed unpaired Student’s t -tests. The da t a underlying this Figure can be found in .
Article Snippet: Vero-E6 (C1008) and L929 (CCL-1) cell lines were purchased from ATCC (USA).
Techniques: Incubation, Infection, Titer Assay, Immunofluorescence, Quantitative RT-PCR, Confocal Microscopy, Virus, Transfection, Over Expression, Single Cell, Binding Assay, Two Tailed Test