Biology:Fas ligand

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.

Structure

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.[1][2]

Simple illustration of the structure of Fas Ligand

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.[3] The soluble form of FasL (sFasL) results from metalloproteinase-mediated proteolytic cleavage of the membrane-bound FasL particularly through matrix metalloproteinase-7 (MMP-7).[4] 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.[5]

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.[6]

Function

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.[7] The Fas receptor changes from its monomeric state to a trimeric form after ligand binding and attracts the FADD (Fas-associated death domain) protein.[8] 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.[9]

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.[10] 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.[11][12]

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.[13][14] The Fas-FasL signaling system operates as apoptotic and non-apoptotic roles because of environmental elements.

Immune privilege

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.[15]

In the eye, for instance, FasL expression by the corneal endothelium and retinal pigment epithelium is responsible for immune tolerance of the transplanted tissues and minimizing immune rejection.[16] Likewise, the testis and placenta employ FasL to shield the germ cells and the developing fetus, respectively, against potentially damaging immune attack.

The function of FasL in immune privilege is not purely protective; anomalous or inordinate FasL expression by these tissues potentially can lead to pathological inflammation or tissue injury.[17] Nevertheless, FasL remains an important aspect of immune evasion, both physiologically as well as pathologically, such as in tumors that simulate the conditions of immune privilege.

Receptor

  • FasR: The Fas receptor (FasR), also known as CD95, is one of the most studied members of the death receptor family. The gene encoding FasR is located on chromosome 10 in humans and chromosome 19 in mice.[18] Studies have identified up to eight splice variants, which give rise to seven different isoforms of the protein. Many of these isoforms are linked to rare haplotypes, often associated with disease states. The apoptosis-inducing Fas receptor, referred to as isoform 1, is a type I transmembrane protein that consists of three cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.[19]
  • DcR3: Decoy receptor 3 (DcR3) is a recently discovered decoy receptor in the tumor necrosis factor (TNF) superfamily. It binds to FasL, LIGHT, and TL1A. DcR3 is a soluble receptor that lacks signal transduction capabilities, hence its name "decoy." It functions to inhibit FasR-FasL interactions by competitively binding to membrane-bound Fas ligand, thereby neutralizing its activity.[20][21]

Expression

Active cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells mainly express Fas ligand to use this molecule for target apoptosis regulation through their immune effector functions.[22][23] Fas ligand localizes to regions of immune privilege including eye and testes and placenta to get rid of invading immune cells thus establishing immunological tolerance.[24]

The regulatory processes for FasL expression function at both transcriptional and post-transcriptional phases. The gene expression of FasL gets controlled by cytokines that include interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) as well as interferon-gamma (IFN-γ).[25] The expression of FasL in immune cells gets significantly enhanced through exposure to stress signals as well as antigen stimulation combined with T cell receptor activation.[26]

Regulation

The expression and function of Fas ligand are regulated tightly at several levels to provide for correct immune responses and avoid tissue injury.

Transcriptional and post-transcriptional control

FasL gene expression is controlled by transcription factors like NFAT (nuclear factor of activated T cells), AP-1 (activator protein 1), and NF-κB. These transcription factors are activated upon T cell receptor (TCR) stimulation, cytokine signaling, and cellular stress.[27] Post-transcriptionally, the stability of FasL mRNA and translation may be controlled by RNA-binding proteins and microRNAs.[28]

Proteolytic cleavage

The cleavage of membrane-bound FasL into its soluble form is facilitated by metalloproteinases, such as matrix metalloproteinase-7 (MMP-7). Cleavage diminishes the apoptotic activity of FasL and can serve to suppress immune responses or rechannel Fas signaling into non-apoptotic pathways.[29]

Intracellular modulators

In the cell, multiple regulatory proteins influence the downstream Fas signaling pathway. c-FLIP, a well-established caspase-8 recruitment inhibitor at the DISC and thus preventing apoptosis, is also present.[30] Protein components in FasL ubiquitination and degradation help regulate its function to fine-tune it.[31]

Signaling pathways

When it binds to its receptor, FasL triggers the classical extrinsic apoptotic pathway but also induces a number of non-apoptotic signal transduction cascades based on the cellular context and availability of intracellular regulatory proteins.[32]

Apoptotic signaling

The apoptotic pathway starts with trimerization of Fas receptor and recruitment of the adaptor molecule FADD. FADD brings about the recruitment of procaspase-8, resulting in the formation of the death-inducing signaling complex (DISC). Activated caspase-8 subsequently activates downstream effector caspases, such as caspase-3, to cause apoptosis through DNA fragmentation, cell shrinkage, and membrane blebbing.[33]

Non-apoptotic signaling

FasL-Fas interaction in certain cell types activates non-apoptotic pathways. These are:

  • NF-κB pathway: Regulates the induction of pro-inflammatory cytokines and anti-apoptotic proteins.[32]
  • MAPK pathways: Regulate cell proliferation, differentiation, and survival.[34] The result of Fas signaling—either apoptotic or non-apoptotic—is governed by the levels of expression of regulatory proteins including c-FLIP, inhibitor of apoptosis proteins (IAPs), and cellular surroundings (e.g., availability of survival factors or immune cytokines). Its dual capability renders Fas signaling versatile and complex in immune modulation and disease.[32] 
Overview of signal transduction pathways involved in apoptosis

Interactions

Fas ligand has been shown to interact with:

Clinical significance

FasL-Fas signaling axis is a central regulator of immune function, and its dysregulation has been implicated in the pathogenesis of many disease processes. Its clinical significance ranges across autoimmune diseases, cancer immunology, and transplant medicine.

Autoimmune diseases

Abnormal Fas-FasL signaling has been linked with survival of autoreactive T cells and B cells, leading to disruption of peripheral immune tolerance.[25] One of the best-studied disorders in this regard is autoimmune lymphoproliferative syndrome (ALPS), a genetic disorder due to mutations in Fas or FasL that leads to lymphocytosis and the emergence of autoimmune disease.[46] Likewise, reduced FasL function has been associated with systemic lupus erythematosus (SLE), where impaired apoptosis of self-reactive cells plays a role in disease etiology.[47]

Signaling pathways of Fas. Dashed grey lines represent multiple steps in JNK signaling.

Cancer

FasL expression by cancer cells is a strategy of immune escape.[48] Several tumor cells express FasL on their surface to trigger apoptosis among Fas-expressing TILs, especially cytotoxic CD8+ T cells.[49] This is called the "Fas counterattack," by which tumors are enabled to evade immune surveillance and proceed with their proliferation.[50] Additionally, the tumor environment can secrete soluble FasL, again contributing to local immunosuppression.[51]

Transplantation

In transplantation environments, FasL participates in both graft tolerance and rejection. Although the expression of FasL within donor tissues can facilitate apoptosis in host immune cells and maintain graft survival,[52] overexpression of FasL can have the opposite effect of causing inflammation and damage to the graft.[53] Experimental evidence has indicated that manipulation of FasL levels would modulate the balance between graft tolerance and rejection.[50]

Evolutionary change

Researchers at the University of California Davis Comprehensive Cancer Center identified a small genetic mutation in FasL that may explain why humans struggle to target solid tumors effectively. This mutation makes FasL more susceptible to deactivation by plasmin, a tumor-associated enzyme. This vulnerability is exclusive to humans and is absent in non-human primates, like chimpanzees.[54]

See also

References

  1. ↑ "CD95 Structure, Aggregation and Cell Signaling". Frontiers in Cell and Developmental Biology 8: 314. 2020. doi:10.3389/fcell.2020.00314. PMID 32432115. 
  2. ↑ "The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors" (in English). Frontiers in Cell and Developmental Biology 8. 2020-10-14. doi:10.3389/fcell.2020.569684. PMID 33163490. 
  3. ↑ Encyclopedia of Immunology (Second ed.). Oxford: Elsevier. January 1998. pp. 874–880. doi:10.1006/rwei.1999.0229. ISBN 978-0-12-226765-9. https://linkinghub.elsevier.com/retrieve/pii/B0122267656002395. Retrieved 2025-04-16. 
  4. ↑ "Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand". Archives of Biochemistry and Biophysics 408 (2): 155–161. December 2002. doi:10.1016/S0003-9861(02)00525-8. PMID 12464266. 
  5. ↑ "Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts". Cells 9 (2): 411. February 2020. doi:10.3390/cells9020411. PMID 32053892. 
  6. ↑ "Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily" (in English). Frontiers in Cell and Developmental Biology 8. 2021-02-11. doi:10.3389/fcell.2020.615141. PMID 33644033. 
  7. ↑ "Nonapoptotic functions of Fas/CD95 in the immune response". The FEBS Journal 285 (5): 809–827. March 2018. doi:10.1111/febs.14292. PMID 29032605. 
  8. ↑ "Structure of the Fas/FADD complex: a conditional death domain complex mediating signaling by receptor clustering". Cell Cycle 8 (17): 2723–2727. September 2009. doi:10.4161/cc.8.17.9399. PMID 19652545. 
  9. ↑ "DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis". Oncogene 28 (18): 1949–1959. May 2009. doi:10.1038/onc.2009.36. PMID 19347032. 
  10. ↑ "Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance" (in English). Frontiers in Immunology 8: 403. 2017-04-05. doi:10.3389/fimmu.2017.00403. PMID 28424702. 
  11. ↑ "Fas/FasL pathway participates in regulation of antiviral and inflammatory response during mousepox infection of lungs". Mediators of Inflammation 2015 (1). 2015. doi:10.1155/2015/281613. PMID 25873756. 
  12. ↑ "The multiple roles of Fas ligand in the pathogenesis of infectious diseases". Clinical Microbiology and Infection 9 (8): 766–779. August 2003. doi:10.1046/j.1469-0691.2003.00669.x. PMID 14616696. 
  13. ↑ "NF-kappa B-dependent Fas ligand expression". European Journal of Immunology 29 (9): 2948–2956. September 1999. doi:10.1002/(SICI)1521-4141(199909)29:09<2948::AID-IMMU2948>3.0.CO;2-0. PMID 10508269. 
  14. ↑ "Non-apoptotic Fas signaling". Cytokine & Growth Factor Reviews 14 (1): 53–66. February 2003. doi:10.1016/S1359-6101(02)00072-2. PMID 12485619. 
  15. ↑ "Fas ligand-induced apoptosis as a mechanism of immune privilege". Science 270 (5239): 1189–1192. November 1995. doi:10.1126/science.270.5239.1189. PMID 7502042. Bibcode: 1995Sci...270.1189G. http://nbn-resolving.de/urn:nbn:de:bsz:352-143183. 
  16. ↑ "Ocular Immune Privilege and Transplantation" (in English). Frontiers in Immunology 7: 37. 2016-02-08. doi:10.3389/fimmu.2016.00037. PMID 26904026. 
  17. ↑ "Fas-ligand: privilege and peril". Proceedings of the National Academy of Sciences of the United States of America 94 (12): 5986–5990. June 1997. doi:10.1073/pnas.94.12.5986. PMID 9177153. Bibcode: 1997PNAS...94.5986G. 
  18. ↑ "Human Fas ligand: gene structure, chromosomal location and species specificity". International Immunology 6 (10): 1567–1574. October 1994. doi:10.1093/intimm/6.10.1567. PMID 7826947. 
  19. ↑ "Crystal Structure of the Complex of Human FasL and Its Decoy Receptor DcR3". Structure 24 (11): 2016–2023. November 2016. doi:10.1016/j.str.2016.09.009. PMID 27806260. 
  20. ↑ "Death and decoy receptors and p53-mediated apoptosis". Leukemia 14 (8): 1509–1513. August 2000. doi:10.1038/sj.leu.2401865. PMID 10942251. 
  21. ↑ "Decoy receptor 3: an endogenous immunomodulator in cancer growth and inflammatory reactions". Journal of Biomedical Science 24 (1). June 2017. doi:10.1186/s12929-017-0347-7. PMID 28629361. 
  22. ↑ "Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes". Journal of Immunology 165 (8): 4367–4371. October 2000. doi:10.4049/jimmunol.165.8.4367. PMID 11035073. 
  23. ↑ "Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells". Journal of Immunology 157 (7): 2909–2915. October 1996. doi:10.4049/jimmunol.157.7.2909. PMID 8816396. 
  24. ↑ "The role of placental Fas ligand in maintaining immune privilege at maternal-fetal interfaces". Seminars in Reproductive Endocrinology 17 (1): 39–44. March 1999. doi:10.1055/s-2007-1016210. PMID 10406074. 
  25. ↑ 25.0 25.1 "Mechanism of activation-induced cell death of T cells and regulation of FasL expression". Critical Reviews in Immunology 34 (4): 301–314. 2014. doi:10.1615/CritRevImmunol.2014009988. PMID 24941158. 
  26. ↑ "Fas and FasL in the homeostatic regulation of immune responses" (in English). Immunology Today 16 (12): 569–574. December 1995. doi:10.1016/0167-5699(95)80079-4. PMID 8579749. 
  27. ↑ "Sequential involvement of NFAT and Egr transcription factors in FasL regulation". Immunity 12 (3): 293–300. March 2000. doi:10.1016/S1074-7613(00)80182-X. PMID 10755616. 
  28. ↑ "mRNA Post-Transcriptional Regulation by AU-Rich Element-Binding Proteins in Liver Inflammation and Cancer". International Journal of Molecular Sciences 21 (18): 6648. September 2020. doi:10.3390/ijms21186648. PMID 32932781. 
  29. ↑ "Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity". Cancer Research 61 (2): 577–581. January 2001. PMID 11212252. https://aacrjournals.org/cancerres/article/61/2/577/507869/Matrix-Metalloproteinase-7-mediated-Cleavage-of. 
  30. ↑ "c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis". The EMBO Journal 21 (14): 3704–3714. July 2002. doi:10.1093/emboj/cdf356. PMID 12110583. 
  31. ↑ "Regulation of death receptor signaling by the ubiquitin system". Cell Death and Differentiation 17 (1): 14–24. January 2010. doi:10.1038/cdd.2009.168. PMID 19893571. 
  32. ↑ 32.0 32.1 32.2 "The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System". Cells 13 (21): 1814. November 2024. doi:10.3390/cells13211814. PMID 39513921. 
  33. ↑ "Caspase-8: regulating life and death". Immunological Reviews 277 (1): 76–89. May 2017. doi:10.1111/imr.12541. PMID 28462525. 
  34. ↑ "Non-apoptotic Fas signaling". Cytokine & Growth Factor Reviews 14 (1): 53–66. February 2003. doi:10.1016/S1359-6101(02)00072-2. PMID 12485619. 
  35. ↑ 35.0 35.1 35.2 35.3 "Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy". The Journal of Biological Chemistry 280 (12): 11641–11647. March 2005. doi:10.1074/jbc.M411781200. PMID 15659383. 
  36. ↑ 36.0 36.1 36.2 "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell 114 (2): 181–190. July 2003. doi:10.1016/s0092-8674(03)00521-x. PMID 12887920. 
  37. ↑ "CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway". The EMBO Journal 19 (19): 5123–5134. October 2000. doi:10.1093/emboj/19.19.5123. PMID 11013215. 
  38. ↑ 38.0 38.1 38.2 "Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)". FEBS Letters 519 (1–3): 50–58. May 2002. doi:10.1016/s0014-5793(02)02709-6. PMID 12023017. 
  39. ↑ 39.0 39.1 "Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor". FEBS Letters 509 (2): 255–262. December 2001. doi:10.1016/s0014-5793(01)03174-x. PMID 11741599. 
  40. ↑ "Interaction of peptides derived from the Fas ligand with the Fyn-SH3 domain". FEBS Letters 373 (3): 265–268. October 1995. doi:10.1016/0014-5793(95)01051-f. PMID 7589480. Bibcode: 1995FEBSL.373..265H. 
  41. ↑ "Identification of amino acid residues important for ligand binding to Fas". The Journal of Experimental Medicine 185 (8): 1487–1492. April 1997. doi:10.1084/jem.185.8.1487. PMID 9126929. 
  42. ↑ "Characterization of Fas (Apo-1, CD95)-Fas ligand interaction". The Journal of Biological Chemistry 272 (30): 18827–18833. July 1997. doi:10.1074/jbc.272.30.18827. PMID 9228058. 
  43. ↑ "A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis". The Journal of Biological Chemistry 274 (20): 13733–13736. May 1999. doi:10.1074/jbc.274.20.13733. PMID 10318773. 
  44. ↑ "Modulation of dendritic cell differentiation and maturation by decoy receptor 3". Journal of Immunology 168 (10): 4846–4853. May 2002. doi:10.4049/jimmunol.168.10.4846. PMID 11994433. 
  45. ↑ "Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer". Nature 396 (6712): 699–703. December 1998. doi:10.1038/25387. PMID 9872321. Bibcode: 1998Natur.396..699P. 
  46. ↑ "Autoimmune Lymphoproliferative Syndrome: An Overview". Archives of Pathology & Laboratory Medicine 144 (2): 245–251. February 2020. doi:10.5858/arpa.2018-0190-RS. PMID 30958694. 
  47. ↑ "The many roles of FAS receptor signaling in the immune system" (in English). Immunity 30 (2): 180–192. February 2009. doi:10.1016/j.immuni.2009.01.001. PMID 19239902. 
  48. ↑ "Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape". Nature Medicine 6 (5): 493–495. May 2000. doi:10.1038/74955. PMID 10802692. 
  49. ↑ "The role of Fas/FasL in immunosuppression induced by human tumors". Cancer Immunology, Immunotherapy 46 (4): 175–184. June 1998. doi:10.1007/s002620050476. PMID 9671140. 
  50. ↑ 50.0 50.1 "Immune evasion by tumours: involvement of the CD95 (APO-1/Fas) system and its clinical implications" (in English). Molecular Medicine Today 4 (2): 63–68. February 1998. doi:10.1016/S1357-4310(97)01191-X. PMID 9547792. 
  51. ↑ "The CD95(APO-1/Fas) DISC and beyond". Cell Death and Differentiation 10 (1): 26–35. January 2003. doi:10.1038/sj.cdd.4401186. PMID 12655293. 
  52. ↑ "Involvement of Fas-Fas ligand interactions in graft rejection". International Reviews of Immunology 18 (5–6): 527–546. January 1999. doi:10.3109/08830189909088497. PMID 10672500. 
  53. ↑ "Accelerated rejection of Fas ligand-expressing heart grafts". Journal of Immunology 162 (1): 518–522. January 1999. doi:10.4049/jimmunol.162.1.518. PMID 9886428. 
  54. ↑ Ely, Isabel (July 3, 2025). "Why Humans Are More Susceptible to Cancer" (in en). http://www.technologynetworks.com/tn/news/why-humans-are-more-susceptible-to-cancer-401868. 

Further reading



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