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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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    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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    • "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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