Cleaved/activated caspase-8 was observed in the transfected cells but there was not expression of Bcl-2 indicated that ORF3a may have a pro-apoptotic function by affecting the extrinsic and not the intrinsic apoptotic pathway. 

The Role of ORF3a protein in apoptosis of host cells: Caspase-8 and Bcl-2

Caspase-8 plays an important role in the extrinsic apoptosis pathway and is an important initiator caspase in the death receptor signaling.

Ohio State University, Columbus

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

Chen, M., & Wang, J. (2002). Initiator caspases in apoptosis signaling pathways. Apoptosis, 7(4), 313-319.

Initiator caspases in apoptosis signaling pathways

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis: Caspase-8

Caspase-9 is an important initiator caspase in a different apoptosis pathway comparted to caspase-8: the mitochondrion-dependent apoptosis.

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis: Caspase-9

Cytochrome C is responsible for the activation of caspase-9 which occurs when cytochrome C that is released into the cytosol binds with Apaf-1 which cleaves and activates caspase-9. Cytochrome C, Apaf-1, and caspase-9 are together referred to as an “apoptosome”.

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis: Cytochrome C

The role of Bid is seen when the death receptor signaling pathway and mitochondrion-dependent apoptosis pathway overlap which begins with the activation/cleavage of Bid to t-Bid (truncated Bid) by caspase 9 and this leads to the release of Cytochrome C into the cytosol (which leads to caspase-9 activation).

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis: Bid/t-Bid

Bcl-2 plays a role in the intrinsic apoptosis pathway by affecting mitochondrial membrane integrity and thereby either triggers or inhibits apoptosis. 

Mechanisms and Key Concepts to Understand Role of ORF3a in Apoptosis: Bcl-2

The presence of specific molecules that play a role in triggering apoptosis was analyzed based on the expression of ORF3a in transfected HEK293T cells. 

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