CD95, also known by its alternative names Fas or APO-1, is a complex protein located on the surface of cells, acting as a receiver for signals from outside the cell. This protein is classified as a transmembrane glycoprotein, meaning it spans the cell membrane and has sugar molecules attached to it. CD95 plays a role in various cellular communication processes, influencing how cells behave and respond to their environment. Its ability to transmit signals across the cell membrane makes it a participant in many fundamental biological activities within the body.
What is CD95?
CD95 is a type I transmembrane glycoprotein that resides on the cell surface, acting as a receptor. Its primary interaction is with its specific binding partner, CD95L. CD95L can exist in two forms: a membrane-bound version and a soluble form. The binding of CD95L to CD95 initiates aggregation of CD95 receptor molecules, triggering various signaling pathways inside the cell.
The extracellular part of the CD95 protein contains three cysteine-rich domains, with the second and third important for CD95L binding. The N-terminal region of CD95’s first cysteine-rich domain includes a pre-ligand assembly domain (PLAD), assisting in receptor clustering. This pre-assembly can influence receptor response to CD95L.
CD95’s Central Role in Programmed Cell Death
CD95 is known for its involvement in programmed cell death, a controlled cell elimination process. Termed apoptosis, this process differs from uncontrolled cell death, removing damaged or unwanted cells efficiently and without inflammation. CD95 acts as a primary initiator of cell death through the extrinsic pathway of apoptosis.
When CD95L binds to the CD95 receptor, it causes CD95 molecules to cluster. This clustering recruits an adaptor protein, Fas-associated protein with death domain (FADD). FADD recruits pro-caspase-8 and pro-caspase-10. This assembly forms the Death-Inducing Signaling Complex (DISC).
Within the DISC, pro-caspases activate each other, becoming active caspase-8 and caspase-10. These activated caspases initiate a cascade of further caspases, including executioner caspases like caspase-3. Their activation leads to the dismantling of the cell, breaking down cellular components and DNA, removing the cell without harming surrounding tissue. This sequence illustrates how CD95 signaling orchestrates cell removal when no longer needed or a threat.
Beyond Apoptosis: Diverse Functions of CD95
While known for programmed cell death, CD95 also participates in other cellular processes. CD95 signaling can influence inflammation, the body’s response to injury or infection, and regulate cell growth and movement. These non-apoptotic functions highlight CD95’s complex signaling capabilities beyond cell death.
The outcome of CD95 activation depends on the cellular environment and the form of its ligand, CD95L. Soluble CD95L, for instance, can trigger different signaling pathways than the membrane-bound form. This soluble ligand may not induce cell death but instead activate pro-survival pathways, such as PI3K and MAPK, which support cell growth and survival.
These non-apoptotic pathways can contribute to cellular behaviors, including cell proliferation, tissue repair, and immune responses. Mechanisms determining CD95 outcomes involve interactions with other proteins and cellular context. This adaptability allows CD95 to serve multiple functions, making it a multifaceted regulator.
CD95 in Human Health and Disease
CD95 signaling dysregulation contributes to various human diseases. In cancer, CD95’s function becomes impaired, preventing tumor cells from undergoing programmed cell death. This failure allows cancerous cells to survive and proliferate, contributing to tumor growth. Some cancer cells may even cleave the N-terminal region of CD95, switching its signaling from pro-apoptotic to pro-survival pathways, supporting tumor development.
Conversely, CD95 signaling is also implicated in autoimmune disorders, where the immune system attacks healthy tissues. Overactive CD95 signaling can lead to excessive cell death and tissue damage in autoimmune conditions. Defective CD95 function can prevent elimination of self-reactive immune cells, leading to their accumulation and autoimmune responses, as seen in autoimmune lymphoproliferative syndrome (ALPS). Balanced CD95 activity is important for immune system regulation and disease prevention.