Cytochrome C, t-Bid, and cleaved/activated caspase-9 were observed in cells with expressed ORF3a and that if an inhibitor was used that inhibited the function of either caspase-8 or caspase-9, there was a drastic reduction in apoptosis of cells with the ORF3a protein. This further cements the proposition that ORF3a plays a role in triggering the extrinsic apoptotic pathway as well as the mechanism that links the death receptor signaling and mitochondrion-dependent apoptosis.

The Role of ORF3a protein in apoptosis of host cells: Other Molecules of Mitochondrion-dependent Apoptosis

Caspase-9 is an important initiator caspase in a different apoptosis pathway comparted to caspase-8: the mitochondrion-dependent 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. https://doi.org/10.1023/a:1016167228059

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

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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