The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
Cell Death Differ
; 14(9): 1678-87, 2007 Sep.
Article
en En
| MEDLINE
| ID: mdl-17557115
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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Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Ácido Aspártico Endopeptidasas
/
Proteínas ADAM
/
Proteína Ligando Fas
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2007
Tipo del documento:
Article