The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany.
Cell Death and Differentiation (Impact Factor: 8.39). 10/2007; 14(9):1678-87. DOI: 10.1038/sj.cdd.4402175
Source: PubMed

ABSTRACT Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidase-like family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

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Available from: Francisca Guardiola Serrano, May 01, 2014
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    • "Within the SPP/SPPL family, a functional relationship between SPPL2a and SPPL2b was suggested [3]. SPPL2a and/or SPPL2b have been implicated in the intramembrane cleavage of TNF-a [3], Bri2 [4] and Fas ligand [5]. SPPL2a and -b are 50% identical and 70% homologous to each other [2]. "
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    ABSTRACT: Signal-peptide-peptidase-like 2A (SPPL2a), an aspartyl intramembrane protease, has been implicated in the proteolysis of TNF-alpha, Fas Ligand and Bri2. Here, we show that endogenous SPPL2a - in agreement with overexpression studies - is localised in membranes of lysosomes/late endosomes. Furthermore, we have analysed the molecular determinants for lysosomal sorting of SPPL2a by creating chimaeric constructs between SPPL2a and its plasma membrane localised homologue SPPL2b. Lysosomal transport of SPPL2a critically depends on its cytosolic carboxyterminal tail. A canonical tyrosine-based sorting motif of the YXXø type at position 498 is sufficient to direct SPPL2a to lysosomal/late endosomal compartments. This motif accounts for the differential localisation of the homologous proteases SPPL2a and SPPL2b and thereby influences the access to substrates and biological function of SPPL2a.
    FEBS letters 09/2011; 585(19):2951-7. DOI:10.1016/j.febslet.2011.08.043 · 3.34 Impact Factor
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    • "Additionally, Kirkin et al. described ADAM10-mediated RIP of FasL, leading to release of an intracellular domain that inhibits gene transcription(Kirkin et al., 2007). These results indicate that ADAM10-mediated FasL cleavage downregulates Fas-mediated apoptosis. "
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    ABSTRACT: Proteolytic processing of transmembrane receptors and ligands can have a dramatic impact on cell signaling processes and subsequent cellular responses, including activation and differentiation. A member of the disintegrin and metalloproteinase family, ADAM10, has emerged as a prominent regulator of numerous receptors and ligands, including Notch and CD23. Here, we review studies resulting from the recent generation of ADAM10 conditional knockout mice which revealed a critical role for ADAM10 in Notch-dependent lymphocyte development. Additionally, we discuss results of numerous in vitro and ex vivo studies indicating that ADAM10 regulates the production of multiple secreted factors that contribute to autoimmune reactions.
    Molecular Immunology 06/2011; 48(11):1319-27. DOI:10.1016/j.molimm.2010.12.005 · 3.00 Impact Factor
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    • "A portion of FasL has also been reported to partition into glycosphingolipid-enriched membrane 'rafts', which may also enhance its death-inducing function(Cahuzac et al., 2006). Extracellular FasL can be cleaved by the metalloproteinase ADAM10, resulting in shedding of a 20-26KDa free extracellular domain, and the intracellular domain can be cleaved and released into the cytosol by the signal peptidase-like protease SPPL2a (Kirkin et al., 2007; Schulte et al., 2007). Soluble FasL released in this way is generally thought to be inactive or even inhibitory for FasLmediated apoptosis, (Jodo et al., 2001; Suda et al., 1997) so metalloproteinase-dependent cleavage could be an inactivating event for FasL function as a membrane-bound ligand. "
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    ABSTRACT: 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.
    Results and problems in cell differentiation 02/2009; 49:17-47. DOI:10.1007/400_2008_24
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