SARS-CoV-2 S, M, and E Structural Glycoproteins Differentially Modulate Endoplasmic Reticulum Stress Responses.
PMID 39940816 | PMCID PMC11816748 | DOI 10.3390/ijms26031047 · International journal of molecular sciences · 2025 · View on PubMed ↗
We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | IFIT1 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | IFIT2 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | ISG15 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | HSPH1 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | HSPA6 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | HSPBP1 | “Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins.” | 0.98 | hgnc_dict_v1 |
| gene | SP1 | “There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein.” | 0.98 | hgnc_dict_v1 |
| gene | MAVS | “There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein.” | 0.98 | hgnc_dict_v1 |
| phenotype | hepatitis C | “We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | COVID-19 | “The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells.” | 0.93 | phenotype_alias_lexicon_v2 |