While many molecules and pathways play a role in apoptosis, in regard to ORF3a’s role in apoptosis, five key molecules need to be explored: Caspase-8, Caspase-9, Cytochrome C, Bid/t-Bid, and Bcl-2.

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis

The effect of the ORF3a protein on apoptosis was investigated by using an apoptosis staining method that involved double staining a culture of cells comprising of Vero E6, HepG2, and HEK293T cells with PI (propidium iodide) and FITC (annexin V-fluorescein 5-isothiocyanate (FITC) where increased staining indicates greater pro-apoptotic activity.

Apoptosis Staining Method: FITC/PI

The ORF3a accessory protein has the ability to trigger apoptosis in SARS-CoV, prompting investigations into its role in SARS-CoV-2. The pro-apoptotic effect of the SARS-CoV-2 ORF3a protein was confirmed in Vero E6, HepG2, and HEK293T cells using staining methods and by tracking key molecules involved in apoptosis pathways.

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Co-occurring mutations have been observed between ORF3a and the region encoding the (S) spike glycoprotein and this may indicate some form of relation in the functions of the S protein and the ORF3a protein. One major function of the ORF3a protein seems to be in apoptosis (or “programmed cell death”) of host cells which will be discussed in further nodes.

Potential Insights of the Function of the ORF3a protein of SARS-CoV2

Apoptosis, which is essentially cell death that is triggered by certain factors, is an important mechanism in the antiviral immune response as it allows the killing of infected cells which aids in limiting and controlling the infection as well as playing a regulatory role in inflammation. Multiple accessory proteins seem to affect apoptosis of host cells and contribute to viral pathogenesis by doing so, making apoptosis an overlapping and overarching concept regarding accessory protein of SARS-CoV2.

Introduction to Apoptosis

Ren, Y., Shu, T., Wu, D. et al. The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cell Mol Immunol 17, 881–883 (2020). https://doi.org/10.1038/s41423-020-0485-9

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