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

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

iScience (2021-12-18)
Jean-Philippe Guégan, Justine Pollet, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Marcus E Peter, Patrick Legembre
ABSTRACT

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. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NF-κB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, which might contribute to remodeling the immune landscape in TNBC cells.

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