Fas and Cell Death: The Basic Story

Fas, also known as CD95, is a receptor on the surface of cells. Its best-known role is as a player in apoptosis, a well-studied form of cell death that is common in a variety of both healthy and disease contexts. Cell death, while scary sounding, is vital in healthy processes like development, response to infections, and normal cellular turnover that happens every day. Failure to properly activate cell death can lead to cancer, autoimmune diseases, and other medical conditions.

Due to its central nature in regulating apoptosis, Fas has been a major target in the development of therapeutics. People have targeted Fas to try to kill cancer cells, while other groups, including ONL Therapeutics, are working to inhibit Fas to prevent cell death.

This is a brief introduction to the role of Fas in apoptosis. To help see the concepts, I’ve made diagrams that depict what’s going on within a target cell and a killing cell.

In a resting state, both cells are happy. In the target cell, Fas floats around the cell membrane. Fas in this state exists as monomers, single inactive units that await their call to action. Similarly, the other players in the cell death scene exist in the cell in their inactive forms. Some are bound to other proteins that prevent their activation. For example, XIAP is bound to the caspases, preventing them from accidentally triggering cell death. Think of how rubber bands are put onto lobster claws to prevent them from causing undesired damage. Likewise, Bax and Bak are kept inactive through a molecular shackle called Bcl-xL.

In the killing cell, things are also in a quiet place. Much like its receptor, Fas Ligand (FasL), the binding partner of the Fas receptor, is in its inactive monomer form, floating around the cell membrane and not causing any problems.

When fate speaks and the target cell is marked for death, the Fas monomers come together in threes to form trimers. These receptor trimers bind to trimers of FasL that form on the killing cell. These combined structures start to form clusters of multiple trimers in a process called oligomerization.

Inside the cell, the trimerization and oligomerization of the Fas receptor results in the recruitment and formation of a complex called the DISC, a staging platform where multiple death signaling pathways stem from. This DISC complex consists of proteins called caspase-8 and FADD. At this point, caspase-8 is activated and begins a cascade of events that will lead to the death of the cell. In one option, caspase-8 can directly activate other caspases, like caspase-3, and result in cell death in a fairly simple pathway.

Or, in another option, caspase-8 can activate a more complex system to kill the cell, one involving the mitochondria. If you remember any of your high school biology, you may remember that the mitochondria are the powerhouses of the cell. In healthy times, they are responsible for the cell’s energy production. However, in this situation, they will be instrumental in the cell’s death.

Once active, caspase-8 can cleave a protein called Bid, the next domino to fall in this pathway. This truncated form of Bid is, perhaps uncreatively, called tBid. The main job of tBid is to liberate Bax and Bak from the inhibitory clutches of Bcl-xL. In their newfound freedom, Bax and Bak poke holes in the outer surface of the mitochondria, triggering a process called mitochondrial outer membrane permeabilization, more commonly referred to by its more onomatopoetically fun acronym: MOMP. This causes the contents of the mitochondria to flow out into the rest of the cell.

In MOMP, two proteins that are normally located inside the mitochondria, Smac and Omi, are released into the body of the cell and bind to XIAP and trigger its destruction. Like cutting the rubber band from the lobster claw, XIAP’s destruction allows pro-caspase-9 to get involved in the death process. It forms a protein complex, dubbed the apoptosome, with Apaf-1 and cytochrome c, another component of the mitochondria that is released during MOMP.

Once the apoptosome is formed, it continues the death cascade and activates additional caspases. These caspases act like molecular scissors and begin cutting and destroying cellular components, ultimately leading to the cell’s death.

This covers the high-level basics of Fas and its relationship to cell death. Future posts will continue to look at Fas and discuss our growing understanding of its roles in a variety of other signaling pathways and processes. Fas does a lot more than its traditional function in cell death. It truly is a fascinating molecule.