Fas ligand#Cell signaling

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.{{cite journal | vauthors = Levoin N, Jean M, Legembre P | title = CD95 Structure, Aggregation and Cell Signaling | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 314 | date = 2020 | pmid = 32432115 | pmc = 7214685 | doi = 10.3389/fcell.2020.00314 | doi-access = free }}{{cite journal | vauthors = Zhao L, Fu Q, Pan L, Piai A, Chou JJ | title = The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors | language = English | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 569684 | date = 2020-10-14 | pmid = 33163490 | pmc = 7591462 | doi = 10.3389/fcell.2020.569684 | doi-access = free }}

File:Fas Ligand (CD95L).png

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.{{cite encyclopedia | vauthors = Alderson MR, Lynch DH | chapter = FAS (CD95) and FAS Ligand |date= January 1998 |encyclopedia=Encyclopedia of Immunology | edition = Second |pages=874–880 | veditors = Delves PJ |url= https://linkinghub.elsevier.com/retrieve/pii/B0122267656002395 |access-date=2025-04-16 |place=Oxford |publisher=Elsevier |doi=10.1006/rwei.1999.0229 |isbn=978-0-12-226765-9 |url-access=subscription }} The soluble form of FasL (sFasL) results from metalloproteinase-mediated proteolytic cleavage of the membrane-bound FasL particularly through matrix metalloproteinase-7 (MMP-7).{{cite journal | vauthors = Vargo-Gogola T, Crawford HC, Fingleton B, Matrisian LM | title = Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand | journal = Archives of Biochemistry and Biophysics | volume = 408 | issue = 2 | pages = 155–161 | date = December 2002 | pmid = 12464266 | doi = 10.1016/S0003-9861(02)00525-8 }} 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.{{cite journal | vauthors = Nareznoi D, Konikov-Rozenman J, Petukhov D, Breuer R, Wallach-Dayan SB | title = Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts | journal = Cells | volume = 9 | issue = 2 | pages = 411 | date = February 2020 | pmid = 32053892 | pmc = 7072292 | doi = 10.3390/cells9020411 | doi-access = free }}

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.{{cite journal | vauthors = Kucka K, Wajant H | title = Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily | language = English | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 615141 | date = 2021-02-11 | pmid = 33644033 | pmc = 7905041 | doi = 10.3389/fcell.2020.615141 | doi-access = free }}

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.{{cite journal | vauthors = Guégan JP, Legembre P | title = Nonapoptotic functions of Fas/CD95 in the immune response | journal = The FEBS Journal | volume = 285 | issue = 5 | pages = 809–827 | date = March 2018 | pmid = 29032605 | doi = 10.1111/febs.14292 }} The Fas receptor changes from its monomeric state to a trimeric form after ligand binding and attracts the FADD (Fas-associated death domain) protein.{{cite journal | vauthors = Salvesen GS, Riedl SJ | title = Structure of the Fas/FADD complex: a conditional death domain complex mediating signaling by receptor clustering | journal = Cell Cycle | volume = 8 | issue = 17 | pages = 2723–2727 | date = September 2009 | pmid = 19652545 | pmc = 2788920 | doi = 10.4161/cc.8.17.9399 }} 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.{{cite journal | vauthors = Olsson M, Vakifahmetoglu H, Abruzzo PM, Högstrand K, Grandien A, Zhivotovsky B | title = DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis | journal = Oncogene | volume = 28 | issue = 18 | pages = 1949–1959 | date = May 2009 | pmid = 19347032 | doi = 10.1038/onc.2009.36 }}

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.{{cite journal | vauthors = Yamada A, Arakaki R, Saito M, Kudo Y, Ishimaru N | title = Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance | language = English | journal = Frontiers in Immunology | volume = 8 | pages = 403 | date = 2017-04-05 | pmid = 28424702 | pmc = 5380675 | doi = 10.3389/fimmu.2017.00403 | doi-access = free }} 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.{{cite journal | vauthors = Bień K, Sokołowska J, Bąska P, Nowak Z, Stankiewicz W, Krzyzowska M | title = Fas/FasL pathway participates in regulation of antiviral and inflammatory response during mousepox infection of lungs | journal = Mediators of Inflammation | volume = 2015 | issue = 1 | pages = 281613 | date = 2015 | pmid = 25873756 | pmc = 4385687 | doi = 10.1155/2015/281613 | doi-access = free }}{{cite journal | vauthors = Dockrell DH | title = The multiple roles of Fas ligand in the pathogenesis of infectious diseases | journal = Clinical Microbiology and Infection | volume = 9 | issue = 8 | pages = 766–779 | date = August 2003 | pmid = 14616696 | doi = 10.1046/j.1469-0691.2003.00669.x | doi-access = free }}

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.{{cite journal | vauthors = Hsu SC, Gavrilin MA, Lee HH, Wu CC, Han SH, Lai MZ | title = NF-kappa B-dependent Fas ligand expression | journal = European Journal of Immunology | volume = 29 | issue = 9 | pages = 2948–2956 | date = September 1999 | pmid = 10508269 | doi = 10.1002/(SICI)1521-4141(199909)29:09<2948::AID-IMMU2948>3.0.CO;2-0 }}{{cite journal | vauthors = Wajant H, Pfizenmaier K, Scheurich P | title = Non-apoptotic Fas signaling | journal = Cytokine & Growth Factor Reviews | volume = 14 | issue = 1 | pages = 53–66 | date = February 2003 | pmid = 12485619 | doi = 10.1016/S1359-6101(02)00072-2 }} 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.{{cite journal | vauthors = Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA | title = Fas ligand-induced apoptosis as a mechanism of immune privilege | journal = Science | volume = 270 | issue = 5239 | pages = 1189–1192 | date = November 1995 | pmid = 7502042 | doi = 10.1126/science.270.5239.1189 | bibcode = 1995Sci...270.1189G | url = http://nbn-resolving.de/urn:nbn:de:bsz:352-143183 }}

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.{{cite journal | vauthors = Taylor AW | title = Ocular Immune Privilege and Transplantation | language = English | journal = Frontiers in Immunology | volume = 7 | pages = 37 | date = 2016-02-08 | pmid = 26904026 | doi = 10.3389/fimmu.2016.00037 | doi-access = free | pmc = 4744940 }} 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.{{cite journal | vauthors = Green DR, Ware CF | title = Fas-ligand: privilege and peril | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 12 | pages = 5986–5990 | date = June 1997 | pmid = 9177153 | pmc = 33671 | doi = 10.1073/pnas.94.12.5986 | doi-access = free | bibcode = 1997PNAS...94.5986G }} 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.

• 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.{{cite journal | vauthors = Takahashi T, Tanaka M, Inazawa J, Abe T, Suda T, Nagata S | title = Human Fas ligand: gene structure, chromosomal location and species specificity | journal = International Immunology | volume = 6 | issue = 10 | pages = 1567–1574 | date = October 1994 | pmid = 7826947 | doi = 10.1093/intimm/6.10.1567 }} 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.{{cite journal | vauthors = Liu W, Ramagopal U, Cheng H, Bonanno JB, Toro R, Bhosle R, Zhan C, Almo SC | title = Crystal Structure of the Complex of Human FasL and Its Decoy Receptor DcR3 | journal = Structure | volume = 24 | issue = 11 | pages = 2016–2023 | date = November 2016 | pmid = 27806260 | doi = 10.1016/j.str.2016.09.009 | doi-access = free }}
• 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.{{cite journal | vauthors = Sheikh MS, Fornace AJ | title = Death and decoy receptors and p53-mediated apoptosis | journal = Leukemia | volume = 14 | issue = 8 | pages = 1509–1513 | date = August 2000 | pmid = 10942251 | doi = 10.1038/sj.leu.2401865 | s2cid = 12572810 | doi-access = }}{{cite journal | vauthors = Hsieh SL, Lin WW | title = Decoy receptor 3: an endogenous immunomodulator in cancer growth and inflammatory reactions | journal = Journal of Biomedical Science | volume = 24 | issue = 1 | pages = 39 | date = June 2017 | pmid = 28629361 | pmc = 5477258 | doi = 10.1186/s12929-017-0347-7 | doi-access = free }}

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.{{cite journal | vauthors = Leite-de-Moraes MC, Herbelin A, Gouarin C, Koezuka Y, Schneider E, Dy M | title = Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes | journal = Journal of Immunology | volume = 165 | issue = 8 | pages = 4367–4371 | date = October 2000 | pmid = 11035073 | doi = 10.4049/jimmunol.165.8.4367 }}{{cite journal | vauthors = Oshimi Y, Oda S, Honda Y, Nagata S, Miyazaki S | title = Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells | journal = Journal of Immunology | volume = 157 | issue = 7 | pages = 2909–2915 | date = October 1996 | pmid = 8816396 | doi = 10.4049/jimmunol.157.7.2909 }} 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.{{cite journal | vauthors = Guller S, LaChapelle L | title = The role of placental Fas ligand in maintaining immune privilege at maternal-fetal interfaces | journal = Seminars in Reproductive Endocrinology | volume = 17 | issue = 1 | pages = 39–44 | date = March 1999 | pmid = 10406074 | doi = 10.1055/s-2007-1016210 }}

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).{{cite journal | vauthors = Arakaki R, Yamada A, Kudo Y, Hayashi Y, Ishimaru N | title = Mechanism of activation-induced cell death of T cells and regulation of FasL expression | journal = Critical Reviews in Immunology | volume = 34 | issue = 4 | pages = 301–314 | date = 2014 | pmid = 24941158 | doi = 10.1615/CritRevImmunol.2014009988 }} 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.{{cite journal | vauthors = Lynch DH, Ramsdell F, Alderson MR | title = Fas and FasL in the homeostatic regulation of immune responses | language = English | journal = Immunology Today | volume = 16 | issue = 12 | pages = 569–574 | date = December 1995 | pmid = 8579749 | doi = 10.1016/0167-5699(95)80079-4 }}

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

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.{{cite journal | vauthors = Rengarajan J, Mittelstadt PR, Mages HW, Gerth AJ, Kroczek RA, Ashwell JD, Glimcher LH | title = Sequential involvement of NFAT and Egr transcription factors in FasL regulation | journal = Immunity | volume = 12 | issue = 3 | pages = 293–300 | date = March 2000 | pmid = 10755616 | doi = 10.1016/S1074-7613(00)80182-X | doi-access = free }} Post-transcriptionally, the stability of FasL mRNA and translation may be controlled by RNA-binding proteins and microRNAs.{{cite journal | vauthors = Dolicka D, Sobolewski C, Correia de Sousa M, Gjorgjieva M, Foti M | title = mRNA Post-Transcriptional Regulation by AU-Rich Element-Binding Proteins in Liver Inflammation and Cancer | journal = International Journal of Molecular Sciences | volume = 21 | issue = 18 | pages = 6648 | date = September 2020 | pmid = 32932781 | pmc = 7554771 | doi = 10.3390/ijms21186648 | doi-access = free }}

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.{{cite journal | vauthors = Mitsiades N, Yu WH, Poulaki V, Tsokos M, Stamenkovic I | title = Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity | journal = Cancer Research | volume = 61 | issue = 2 | pages = 577–581 | date = January 2001 | pmid = 11212252 | url = https://aacrjournals.org/cancerres/article/61/2/577/507869/Matrix-Metalloproteinase-7-mediated-Cleavage-of }}

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.{{cite journal | vauthors = Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S, Peter ME, Yang X | title = c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis | journal = The EMBO Journal | volume = 21 | issue = 14 | pages = 3704–3714 | date = July 2002 | pmid = 12110583 | pmc = 125398 | doi = 10.1093/emboj/cdf356 }} Protein components in FasL ubiquitination and degradation help regulate its function to fine-tune it.{{cite journal | vauthors = Wertz IE, Dixit VM | title = Regulation of death receptor signaling by the ubiquitin system | journal = Cell Death and Differentiation | volume = 17 | issue = 1 | pages = 14–24 | date = January 2010 | pmid = 19893571 | doi = 10.1038/cdd.2009.168 }}

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.{{cite journal | vauthors = Seyrek K, Espe J, Reiss E, Lavrik IN | title = The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System | journal = Cells | volume = 13 | issue = 21 | pages = 1814 | date = November 2024 | pmid = 39513921 | pmc = 11545656 | doi = 10.3390/cells13211814 | doi-access = free }}

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.{{cite journal | vauthors = Tummers B, Green DR | title = Caspase-8: regulating life and death | journal = Immunological Reviews | volume = 277 | issue = 1 | pages = 76–89 | date = May 2017 | pmid = 28462525 | pmc = 5417704 | doi = 10.1111/imr.12541 }}

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.
• MAPK pathways: Regulate cell proliferation, differentiation, and survival.{{cite journal | vauthors = Wajant H, Pfizenmaier K, Scheurich P | title = Non-apoptotic Fas signaling | journal = Cytokine & Growth Factor Reviews | volume = 14 | issue = 1 | pages = 53–66 | date = February 2003 | pmid = 12485619 | doi = 10.1016/S1359-6101(02)00072-2 }} 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. 

Image:Signal transduction pathways.svg]]

Fas ligand has been shown to interact with:

{{div col|colwidth=20em}}

• CASP8,
• EZR,{{cite journal | vauthors = Parlato S, Giammarioli AM, Logozzi M, Lozupone F, Matarrese P, Luciani F, Falchi M, Malorni W, Fais S | title = CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway | journal = The EMBO Journal | volume = 19 | issue = 19 | pages = 5123–5134 | date = October 2000 | pmid = 11013215 | pmc = 302100 | doi = 10.1093/emboj/19.19.5123 }}
• FADD,{{cite journal | vauthors = Gajate C, Mollinedo F | title = Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy | journal = The Journal of Biological Chemistry | volume = 280 | issue = 12 | pages = 11641–11647 | date = March 2005 | pmid = 15659383 | doi = 10.1074/jbc.M411781200 | doi-access = free }}{{cite journal | vauthors = Micheau O, Tschopp J | title = Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes | journal = Cell | volume = 114 | issue = 2 | pages = 181–190 | date = July 2003 | pmid = 12887920 | doi = 10.1016/s0092-8674(03)00521-x | s2cid = 17145731 }}
• FNBP1,
• FYN,{{cite journal | vauthors = Hane M, Lowin B, Peitsch M, Becker K, Tschopp J | title = Interaction of peptides derived from the Fas ligand with the Fyn-SH3 domain | journal = FEBS Letters | volume = 373 | issue = 3 | pages = 265–268 | date = October 1995 | pmid = 7589480 | doi = 10.1016/0014-5793(95)01051-f | s2cid = 24130275 | doi-access = free | bibcode = 1995FEBSL.373..265H }}
• FAS,{{cite journal | vauthors = Starling GC, Bajorath J, Emswiler J, Ledbetter JA, Aruffo A, Kiener PA | title = Identification of amino acid residues important for ligand binding to Fas | journal = The Journal of Experimental Medicine | volume = 185 | issue = 8 | pages = 1487–1492 | date = April 1997 | pmid = 9126929 | pmc = 2196280 | doi = 10.1084/jem.185.8.1487 }}{{cite journal | vauthors = Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A, Peitsch MC, Tschopp J | title = Characterization of Fas (Apo-1, CD95)-Fas ligand interaction | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18827–18833 | date = July 1997 | pmid = 9228058 | doi = 10.1074/jbc.272.30.18827 | doi-access = free }}
• Grb2,{{cite journal | vauthors = Ghadimi MP, Sanzenbacher R, Thiede B, Wenzel J, Jing Q, Plomann M, Borkhardt A, Kabelitz D, Janssen O | title = Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178) | journal = FEBS Letters | volume = 519 | issue = 1–3 | pages = 50–58 | date = May 2002 | pmid = 12023017 | doi = 10.1016/s0014-5793(02)02709-6 | s2cid = 26765451 }}{{cite journal | vauthors = Wenzel J, Sanzenbacher R, Ghadimi M, Lewitzky M, Zhou Q, Kaplan DR, Kabelitz D, Feller SM, Janssen O | title = Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor | journal = FEBS Letters | volume = 509 | issue = 2 | pages = 255–262 | date = December 2001 | pmid = 11741599 | doi = 10.1016/s0014-5793(01)03174-x | s2cid = 33084576 | doi-access = }}
• PACSIN2, and
• TNFRSF6B.{{cite journal | vauthors = Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS | title = A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis | journal = The Journal of Biological Chemistry | volume = 274 | issue = 20 | pages = 13733–13736 | date = May 1999 | pmid = 10318773 | doi = 10.1074/jbc.274.20.13733 | doi-access = free }}{{cite journal | vauthors = Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC, Chen L, Hsieh SL | title = Modulation of dendritic cell differentiation and maturation by decoy receptor 3 | journal = Journal of Immunology | volume = 168 | issue = 10 | pages = 4846–4853 | date = May 2002 | pmid = 11994433 | doi = 10.4049/jimmunol.168.10.4846 | doi-access = free }}{{cite journal | vauthors = Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A | title = Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer | journal = Nature | volume = 396 | issue = 6712 | pages = 699–703 | date = December 1998 | pmid = 9872321 | doi = 10.1038/25387 | s2cid = 4427455 | bibcode = 1998Natur.396..699P }}

{{Div col end}}

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.

Abnormal Fas-FasL signaling has been linked with survival of autoreactive T cells and B cells, leading to disruption of peripheral immune tolerance. 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.{{cite journal | vauthors = Matson DR, Yang DT | title = Autoimmune Lymphoproliferative Syndrome: An Overview | journal = Archives of Pathology & Laboratory Medicine | volume = 144 | issue = 2 | pages = 245–251 | date = February 2020 | pmid = 30958694 | pmc = 10415410 | doi = 10.5858/arpa.2018-0190-RS }} 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.{{cite journal | vauthors = Strasser A, Jost PJ, Nagata S | title = The many roles of FAS receptor signaling in the immune system | language = English | journal = Immunity | volume = 30 | issue = 2 | pages = 180–192 | date = February 2009 | pmid = 19239902 | pmc = 2956119 | doi = 10.1016/j.immuni.2009.01.001 }}

Image:Fas signaling.jpg

FasL expression by cancer cells is a strategy of immune escape.{{cite journal | vauthors = Restifo NP | title = Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape | journal = Nature Medicine | volume = 6 | issue = 5 | pages = 493–495 | date = May 2000 | pmid = 10802692 | pmc = 1955754 | doi = 10.1038/74955 }} Several tumor cells express FasL on their surface to trigger apoptosis among Fas-expressing TILs, especially cytotoxic CD8+ T cells.{{cite journal | vauthors = Whiteside TL, Rabinowich H | title = The role of Fas/FasL in immunosuppression induced by human tumors | journal = Cancer Immunology, Immunotherapy | volume = 46 | issue = 4 | pages = 175–184 | date = June 1998 | pmid = 9671140 | pmc = 11037378 | doi = 10.1007/s002620050476 }} This is called the "Fas counterattack," by which tumors are enabled to evade immune surveillance and proceed with their proliferation.{{cite journal | vauthors = Strand S, Galle PR | title = Immune evasion by tumours: involvement of the CD95 (APO-1/Fas) system and its clinical implications | language = English | journal = Molecular Medicine Today | volume = 4 | issue = 2 | pages = 63–68 | date = February 1998 | pmid = 9547792 | doi = 10.1016/S1357-4310(97)01191-X }} Additionally, the tumor environment can secrete soluble FasL, again contributing to local immunosuppression.{{cite journal | vauthors = Peter ME, Krammer PH | title = The CD95(APO-1/Fas) DISC and beyond | journal = Cell Death and Differentiation | volume = 10 | issue = 1 | pages = 26–35 | date = January 2003 | pmid = 12655293 | doi = 10.1038/sj.cdd.4401186 }}

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,{{cite journal | vauthors = Martinez OM, Krams SM | title = Involvement of Fas-Fas ligand interactions in graft rejection | journal = International Reviews of Immunology | volume = 18 | issue = 5–6 | pages = 527–546 | date = January 1999 | pmid = 10672500 | doi = 10.3109/08830189909088497 }} overexpression of FasL can have the opposite effect of causing inflammation and damage to the graft.{{cite journal | vauthors = Takeuchi T, Ueki T, Nishimatsu H, Kajiwara T, Ishida T, Jishage K, Ueda O, Suzuki H, Li B, Moriyama N, Kitamura T | title = Accelerated rejection of Fas ligand-expressing heart grafts | journal = Journal of Immunology | volume = 162 | issue = 1 | pages = 518–522 | date = January 1999 | pmid = 9886428 | doi = 10.4049/jimmunol.162.1.518 }} Experimental evidence has indicated that manipulation of FasL levels would modulate the balance between graft tolerance and rejection.

• FAF1

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Choi C, Benveniste EN | title = Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses | journal = Brain Research. Brain Research Reviews | volume = 44 | issue = 1 | pages = 65–81 | date = January 2004 | pmid = 14739003 | doi = 10.1016/j.brainresrev.2003.08.007 | s2cid = 46587211 }}
• {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef | journal = Current HIV Research | volume = 2 | issue = 2 | pages = 141–151 | date = April 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alps GeneReviews/NCBI/NIH/UW entry on Autoimmune Lymphoproliferative Syndrome]
• {{OMIM|601859}}
• {{MeshName|Fas+Ligand+Protein}}
• {{PDBe-KB2|P48023|Tumor necrosis factor ligand superfamily member 6}}

{{Clusters of differentiation}}

{{Tumor necrosis factors}}

{{Fas apoptosis signaling pathway}}

{{Cytokine receptor modulators}}

Category:Clusters of differentiation

Category:Immune system

Category:Programmed cell death

Category:Signal transduction