Fas ligand

Fas ligand (FasL, also known as CD95L or Apo-1L) is a type-II transmembrane protein in the tumor necrosis factor (TNF) superfamily. It binds to the Fas receptor (CD95) to induce apoptosis, and also activates non-apoptotic pathways such as NF-κB and MAPK. FasL exists in membrane-bound and soluble forms, and is primarily expressed by cytotoxic T lymphocytes and natural killer cells. It plays a critical role in immune regulation, immune privilege, cancer, autoimmunity, and transplantation. The expression and function of FasL are tightly regulated to maintain immune homeostasis.

Fas ligand operates as a type-II transmembrane protein through its membership in the tumor necrosis factor (TNF) superfamily. It operates under its official names FasL and CD95L or Apo-1L. With 281 amino acids the protein forms three identifiable structural components by including an intracellular N-terminal domain then follows with one transmembrane domain that leads to an extracellular C-terminal domain. The FasL binding activity rests in its extracellular domain which triggers Fas receptor engagement to start apoptotic signals.

The biological existence of FasL occurs through two different forms which are membrane-bound and soluble. The membrane-bound protein exists as three identical subunits which serve as both the receptor activation mechanism and primary factor for complete apoptotic functionality. The soluble form of FasL (sFasL) results from metalloproteinase-mediated proteolytic cleavage of the membrane-bound FasL particularly through matrix metalloproteinase-7 (MMP-7). Despite its ability to attach with Fas receptors the soluble form of FasL possesses much less potency for apoptosis induction while researchers assume it functions to modify immune system activities.

The apoptosis-relevant domain known as TNF homology domain (THD) enables FasL structural features common to other members of TNF family protein ligands to promote both receptor interaction and trimer formation. The structural properties enable the ligand to fulfill its biological role and its selective killing of Fas-expressing cells.

As the principal goal of Fas ligand exists to trigger target cell apoptotic processes by binding to its receptor Fas (CD95) which is present on numerous cell types. The Fas receptor changes from its monomeric state to a trimeric form after ligand binding and attracts the FADD (Fas-associated death domain) protein. The recruitment of procaspase-8 occurs through FADD until the death-inducing signaling complex (DISC) is formed. The DISC complex triggers a succession of activated caspases that perform substrate cleavage activities resulting in apoptotic cellular break down.

FasL-mediated apoptosis plays several important biological functions in human physiology. The peripheral immune system depends on FasL to function properly because it removes lymphocytes that attack themselves. The immune response contraction phase is dependent on FasL because this molecule acts as a key factor to eliminate activated lymphocytes after pathogen elimination. FasL enables homeostatic maintenance of tissues by causing elimination of virus-infected cells and cells with transformed potential.

The apoptosis-related role of FasL has been identified while scientists have also discovered that FasL activates both NF-κB and MAPK signaling pathways that support cell survival conditions and cause cellular inflammation and proliferation. The Fas-FasL signaling system operates as apoptotic and non-apoptotic roles because of environmental elements.

Fas ligand is a principal mediator of immune privilege, an immunoregulatory process found in some tissues to shield them from immune-mediated destruction. Immune-privileged sites are the eye, brain, testis, and placenta. These tissues express FasL constitutively or upon local immune stimulation to kill invading Fas-expressing lymphocytes by apoptosis.