Abstract
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 socalled “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 activationdependent 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.
Keywords: Fas ligand, PCH protein family, Nck, secretory lysosome, activation-induced cell death, apoptosis, reverse signalling, TNF family
Current Medicinal Chemistry
Title: Storage, Expression and Function of Fas Ligand, the Key Death Factor of Immune Cells
Volume: 15 Issue: 17
Author(s): Marcus Lettau, Maren Paulsen, Dieter Kabelitz and Ottmar Janssen
Affiliation:
Keywords: Fas ligand, PCH protein family, Nck, secretory lysosome, activation-induced cell death, apoptosis, reverse signalling, TNF family
Abstract: 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 socalled “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 activationdependent 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.
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Lettau Marcus, Paulsen Maren, Kabelitz Dieter and Janssen Ottmar, Storage, Expression and Function of Fas Ligand, the Key Death Factor of Immune Cells, Current Medicinal Chemistry 2008; 15 (17) . https://dx.doi.org/10.2174/092986708784872384
DOI https://dx.doi.org/10.2174/092986708784872384 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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