Metalloprotease‐mediated cleavage of CD95 ligand

Abstract

CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand CD95L induces its oligomerization leading in turn to the transduction of either apoptotic or nonapoptotic signals. CD95L can exist as both membrane‐anchored and soluble forms (sCD95L), the latter resulting from the proteolytic cleavage of the former. Candidate proteases able to achieve CD95L cleavage were identified as matrix metalloproteases (MMP) due to their demonstrated ability to cleave other TNF superfamily ligands. The main goal of this study was to systematically identify the MMP family members capable of cleaving CD95L and subsequently determine the corresponding cleavage sites. By using different orthogonal biochemical approaches and combining them with molecular modelling, we confirmed data from the literature regarding CD95L cleavage by MMP‐3 and MMP‐7. Moreover, we found that MMP‐2 and MMP‐12 can cleave CD95L and characterized their resulting cleavage sites. This study provides a systematic approach to analyse the cleavage of CD95L, which until now had only been poorly described.

IRE1 RNase controls CD95-mediated cell death

“…CD95 can also mediate a variety of non-cytotoxic pro-tumoural cellular outcomes, including migration, production of pro-inflammatory cytokines, proliferation and regulation of cell differentiation state, which are also modulated by IRE1 signalling (Annibaldi and Walczak, 2020 ; Risso et al, 2022 ; Rossin et al, 2019 ). Therefore, it is likely that IRE1-mediated CD95 increased expression could contribute to tumour progression in cancer cells which display primary or acquired resistance to CD95L-induced cell death.…”

“…Amongst those are the signalling engaged by the death receptors (DR) and the unfolded protein response (UPR), an adaptive response to endoplasmic reticulum (ER) stress. The DR TRAIL-R1/2 and CD95 (also known as FAS) contribute to the immunosurveillance towards cancer or infected cells by their ability to induce cell death upon engagement by their ligand, TRAIL and CD95L, respectively (Von Karstedt et al, 2017 ; Rossin et al, 2019 ; Risso et al, 2022 ). In some tumour cells however, engagement of CD95 or TRAIL-R1/2 fails to induce cell death and promotes pro-tumorigenic cellular outcomes.…”