Role of metalloproteases in the CD95 signaling pathways

Abstract

CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed.

CD95L concatemers highlight different stoichiometries of CD95‐mediated apoptotic and nonapoptotic pathways

“…3A and C). CD95L can be cleaved by different metalloproteases and at different positions in its stalk region [13] such as 113 EL 114 [23], 126 SL 127 [3, 4], or 129 KQ 130 [24, 25] according to the literature. We previously observed that the metalloprotease‐driven cleavage of CD95L in HEK/293T cells mainly occurs between aa residues 126 SL 127 [4] and thereby leads to the elimination of a large part of its stalk region.…”

“…3A and C). CD95L can be cleaved by different metalloproteases and at different positions in its stalk region [13] such as 113 EL 114 [23], 126 SL 127 [3,4], or 129 KQ 130 [24,25] according to the literature.…”

“…Oxidation of the unique methionine present in the CD95L stalk region at position 121 does not modify the magnitude of self-aggregation but it prevents the cleavage of mCD95L between 126 SL 127 by MMP7 and promotes its processing closer to its plasma membrane [13]. The released soluble CD95L is longer, and it shows a stronger ability to kill epithelial cells as compared to the MMP7-cleaved ligand [13]. Overall, these results suggest that not only the stoichiometry of CD95L but also the conservation of its stalk region might account for the induction of robust apoptotic and nonapoptotic responses [14][15][16][17].…”

The Dual Function of RhoGDI2 in Immunity and Cancer

“…MMPs are ECM-degrading enzymes involved in tumour invasion and metastasis. They are also intimately involved in the regulation of the activities of cytokines and cytokine receptors [ 95 ]. No further research was conducted to delve into the relation between RhoGDI2 and PI3K/Akt pathway in HCC [ 35 ].…”

CD95L concatemers highlight difference in the manner CD95-mediated apoptotic and non-apoptotic pathways are triggered

“…3A and 3C). CD95L can be cleaved by different metalloproteases and at different positions in its stalk region (24) such as 113 EL 114 (25), 126 SL 127 (3,4) or 129 KQ 130 (26,27) according to the literature. We previously observed that the metalloprotease-driven cleavage of CD95L in HEK/293T cells mainly occurs between amino acid residues 126 SL 127 (4) and thereby leads to the elimination of a part of the CD95L stalk region.…”