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

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

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

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

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

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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