CD95/Fas suppresses NF-κB activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism

CD95 expression is preserved in triple-negative breast cancers (TNBCs), and CD95 loss in these cells triggers the induction of a pro-inflammatory program, promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2), using an unbiased proteomic approach. Independextly of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NF-kappa B1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-kappa B-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit ReIA (p65) and KPC1, which acts as E3 ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-kappa B inhibitory homodimer complex (p50/p50), promoting NF-kappa B activation and the production of pro-inflammetory cytokines, which might contribute to remodeling the immune landscape in TNBC cells.