Many checkpoints on the road to cell death: regulation of Fas-FasL interactions and Fas signaling in peripheral immune responses.
Interactions between the TNF-family receptor Fas (CD95) and Fas Ligand (FasL, CD178) can efficiently induce apoptosis and are critical for the maintenance of immunological self-tolerance. FasL is kept under strict control by transcriptional and posttranslational regulation. Surface FasL can be cleaved by metalloproteases, resulting in shed extracellular domains, and FasL can also traffic to secretory lysosomes. Each form of FasL has distinct biological functions. Fas is more ubiquitously expressed, but its apoptosis-inducing function is regulated by a number of mechanisms including submembrane localization, efficiency of receptor signaling complex assembly and activation, and bcl-2 family members in some circumstances. When apoptosis is not induced, Fas-FasL interactions can also trigger a number of activating and proinflammatory signals. Harnessing the apoptosis-inducing potential of Fas for therapy of cancer and autoimmune disease has been actively pursued, and despite a number of unexpected side-effects that result from manipulating Fas-FasL interactions, this remains a worthy goal.
Ramaswamy
Madhu
M
Immunoregulation Unit, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda MD 20892, USA.
Cleland
Sophia Y
SY
Cruz
Anthony C
AC
Siegel
Richard M
RM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor