Fig 1: Thapsigargin regulates a specific network of proteins involved in transport, ERQC/ERAD, and ER stress in MERS-CoV or SARS-CoV-2-infected cells.a Overlap of orthologous proteins expressed in HuH7 and Vero cells. b Overlap of virus- and thapsigargin-regulated proteins common to HuH7 and Vero E6 cells showing 120 proteins with higher and 63 proteins with lower expression in thapsigargin-treated infected cells compared to virus infection alone (ratio > 0, p value of -log10 (p) = 1.3). c Heatmaps showing individual mean ratio values of normalized protein intensities for the top 50 up- or downregulated proteins in virus-infected and thapsigargin-treated cells. Ratio values of infected or thapsigargin-treated conditions compared to untreated cells (-) are shown for comparison and are sorted according to the virus plus thapsigargin conditions. Green colors highlight HERPUD1 and BiP (HSPA5), while orange colors highlight p62/SQSTM1. d Top pathways mapping to gene IDs with increased (120 proteins, red) or decreased (63 proteins, blue) expression levels in thapsigargin-treated and infected cells compared to virus infection alone as revealed by overrepresentation analysis using Metascape software44. e Protein:protein interactions (PPI) amongst the 120 up- and 63 downregulated thapsigargin-sensitive proteins based on experimental evidence, co-occurrence, co-expression, and confidence scores from the STRING database108. According to experimental evidence and combined STRING score criteria, 71 and 26 coregulated proteins are engaged in defined PPI networks; the remaining proteins are not known to interact. f Heatmap showing thapsigargin-reprogrammed proteins of KEGG hsa04141 (mean ratio = 1.5 fold). See also Supplementary Fig. 9 for projection of thapsigargin-mediated protein changes on the KEGG pathway map. g Venn diagram showing the intersection of thapsigargin-/virus-regulated proteins with all novel ERAD components (FDR of 1%) identified by ref. 50. The regulation of 30 overlapping components is shown as a heatmap displaying mean ratio values in thapsigargin-treated or infected cells. Red colors highlight UBA6 and ZNF622 as discussed in the text. (b, c, f, g) Mean ratio and p values were determined as described in the legend of Fig. 6a–d. Abbreviations: M MERS-CoV; S SARS-CoV-2; T thapsigargin.