Posttranslational regulation of Fas ligand function

Fas ligand (FasL, APO-1L, CD95L, CD178) belongs to the tumour necrosis factor (TNF) superfamily of type II transmembrane proteins [1]. It was initially cloned from a T cell hybridoma that strongly bound murine Fas-Fc fusion proteins [2]. Binding of membrane-bound FasL to Fas/APO-1/CD95-expressing target cells triggers a well-characterised pro-apoptotic signalling cascade eventually leading to caspase activation and cell death [3,4]. As a potent death factor, FasL is employed by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to selectively kill virus infected or tumourigenic cells and thus complements the perforin/granzyme-dependent effector pathway [5]. Of note, however, beside these two generally accepted key pathways, recent evidence also suggested a significant contribution of TNF-related apoptosis-inducing ligand (TRAIL) in target cell destruction, for example during CTL-mediated clearance of influenza virus infected cells [6].Apart from its involvement in CTL- and NK cell-mediated cell death, the FasL/Fas system is of particular importance for the immune homeostasis. Its role in down-regulation of immune responses during activation-induced cell death (AICD) is well documented [3,7]. It is underscored by the pathologic phenotypes of naturally occurring Fas- and FasL-deficient mice (lpr/lpr and gld/gld, respectively), which are defective in AICD and suffer from lymphoproliferative syndromes [8]. Of course, AICD is a complex process that besides the involvement of the FasL/Fas system is further controlled by a number of activation-dependent cytokines, intracellular pro- or anti-apoptotic regulators such as for example Bcl-2 family proteins and signalling molecules like the hematopoietic progenitor kinase (HPK) [9].Although still a matter of debate with regard to its physiological relevance, FasL expression has been observed in immune-privileged tissues such as the anterior chamber of the eye, as well as in neurons and astrocytes of the central nervou