The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells.
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.
Kirkin
V
V
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany.
Cahuzac
N
N
Guardiola-Serrano
F
F
Huault
S
S
Lückerath
K
K
Friedmann
E
E
Novac
N
N
Wels
W S
WS
Martoglio
B
B
Hueber
A-O
AO
Zörnig
M
M
D051722:ADAM Proteins / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000378:metabolism*
D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D016282:Aspartic Acid Endopeptidases; C524670:SPPL2a protein, human; D051722:ADAM Proteins