SARS-CoV-2 Accessory Protein ORF7b Mediates Tumor Necrosis Factor-α-Induced Apoptosis in Cells

Abstract

The accessory proteins of coronaviruses are essential for virus–host interactions and the modulation of host immune responses. It has been reported that accessory protein ORF3a encoded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce apoptosis, and accessory protein ORF6 and ORF8 could be inhibitors of the type-I interferon (IFN) signaling pathway. However, the function of accessory protein ORF7b is largely unknown. We investigated the apoptosis-inducing activity of ORF7b in cells. Cytokine levels and host innate immune responses, including expression of interferon regulatory transcription factor (IRF)-3, signal transducer and activator of transcription (STAT)-1, interferon (IFN)-β, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were also investigated. We found that ORF7b promoted expression of IFN-β, TNF-α, and IL-6, activated type-I IFN signaling through IRF3 phosphorylation, and activated TNFα-induced apoptosis in HEK293T cells and Vero E6 cells. These results could provide deeper understanding about the pathogenicity of SARS-CoV-2 as well as the interaction between the accessory protein ORF7b with host immune responses.

Expansion of a SARS-CoV-2 Delta variant with an 872 nt deletion encompassing ORF7a, ORF7b and ORF8, Poland, July to August 2021

“…ORF7a activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) pathway and induces proinflammatory cytokine expression [ 19 , 20 ]. The function of ORF7b is largely unknown, but a recent study has shown that the protein activates the type-I interferon (IFN) signalling pathway and promotes expression of IFN-beta, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha, which induce apoptosis [ 21 ]. Viruses lacking these genes also produced smaller plaques than WT viruses in vitro, but their growth kinetics were similar to the parental strain [ 13 ].…”

Relationship between miR-338-3p and Clinicopathological Parameters, Prognosis, and STAT3 mRNA Expression in Nasopharyngeal Carcinoma

“…STAT, a family of proteins with special significance in cells, is encoded by the STAT gene and is an important transcription factor in the process of cell proliferation, maturation, and survival. It can affect the proliferation of tumor cells and normal cells, help promote the metastasis and differentiation of tumor cells, and inhibit the apoptosis of tumor cells [ 23 ]. Among them, STAT3 is most closely related to cancer, and its abnormal activation is closely related to the occurrence and development of a variety of human malignant tumors, such as leukemia, lymphoma, prostate cancer, and all kinds of head and neck tumors and gastrointestinal tumors as well as to immune tolerance in the tumor microenvironment [ 24 ].…”

Subcellular mapping of the protein landscape of SARS-CoV-2 infected cells for target-centric drug repurposing

“…The M protein is one of the structural components common to all coronaviruses. ORF3 and ORF7B belong to the accessory factors, which tend to be non-essential for viral replication, but important for pathogenesis and virus-host interactions (24,25), and both ORF3 and ORF7B have been shown to modulate host cell immune responses (26,27). The host responses to SARS-CoV-2 are associated with multiple cellular components and diverse cellular functions ( Figure 1B ).…”