Question

Describe the process of a white blood cell activating a death receptor such as TNFR or Fas on a target cell. Specifically mention the role of Bax, Bak, MMP, and caspases.

Answer 1

Macrophages are a type of white blood cells on activation produces cytokines such as TNF-alpha. TNF-alpha binds to death receptors such as TNF receptors family and initiates apoptosis also known as programmed cell death.These receptors (TNFR-1, Fas) are located in the cell membrane and upon activation by TNF-alpha trimerises and recruit an adapter protein that complexes with trimer by associating with the death domains (TNF receptor-associated death domain (TRADD) and Fas-associated death domain protein (FADD)) present in the cytoplasmic tail. This leads to the activation of caspase-8 enzyme which in turn activates effector caspases such as caspase-3. Caspase-3 inactivates enzymes and essential structural components of cell, fragmentation of genomic DNA and leads to cell death.

Mammalian mitochondrial membrane permeation is regulated by members of the Bcl-2 family such as proapoptotic (BAX, BAK) and anti-apoptotic (Bcl-Xl and Bcl-2). TNF-R1 and Fas activation leads to the production of proapoptotic BAX and BAK molecules which in turn releases caspase enzyme activators such as cytochrome c and SMAC. By producing caspase-8, BAX and BAK plays main role in apoptosis.

Mitochondrial membrane permeabilization (MMP), is a rate-limiting step in the execution of the death process and many signals from mitochondria converges to regulate the permeability of mitochondrial membrane. Bcl-2 family members such as proapoptotic (BAX, BAK) and anti-apoptotic (Bcl-Xl and Bcl-2) proteins regulate MMP and balance of these molecules decides whether the cell dies or not.

Caspases are a family of protease enzymes playing essential roles in apoptosis. They are grouped in to two. Initiator caspases (Caspase 8, Caspase 9) and effector caspases (Caspase 3, Caspase 6). Cytochrome c released to cytosol and binds an adaptor protein (APAF-1) leads to the activation of caspase-9. Once initiator caspases are activated, they produce a chain reaction, activating several other executioner caspases such as caspase3 and 6. Executioner caspases inactivates enzymes and essential structural components of cell, fragmentation of genomic DNA and leads to cell death.