Storage, expression and function of Fas ligand, the key death factor of immune cells.

Marcus Lettau, Maren Paulsen, Dieter Kabelitz, Ottmar Janssen
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Current medicinal chemistry : the new international journal for timely in-depth reviews in medical chemistry
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The TNF family member Fas ligand (FasL) induces apoptosis in Fas-expressing cells and serves as a key death factor in the immune system. It is involved in the termination of immune responses by activation-induced cell death, the selection of thymocytes and T and NK cell-mediated cytotoxicity. FasL also participates in the establishment of immune privilege and contributes to tumor cell survival. Besides its death-inducing capacity, FasL has been implicated in retrograde signal transduction into FasL expressing cells by so-called "reverse signalling". In this context, FasL may also act as an accessory/costimulatory molecule. Dysregulation within the Fas/FasL-system manifests in a severe impairment of the functional integrity and maintenance of immune homeostasis. As its receptor Fas is abundantly expressed in several tissues, the expression of FasL has to be tightly regulated to prevent unwanted damage. At the post-transcriptional level, this is achieved by several independent mechanisms, for example the safe intracellular storage, an activation-dependent mobilization, the association with lipid rafts and the shedding by metalloproteases. Of interest, the intracellular portion of FasL contains a unique proline-rich domain, which plays a major role in the control of FasL transport and expression due to interactions with proteins containing SH3 or WW interaction domains. The detailed analysis of FasL-interacting proteins and their functional characterization provided novel insights into the complex processes regulating FasL expression and signal transduction. This knowledge should allow to improve Fas/FasL-based therapeutical approaches that are currently under development.