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

Jean Philippe Guégan, Justine Pollet, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Marcus E. Peter, Patrick Legembre*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Article number103538
Issue number12
StatePublished - Dec 17 2021


  • Cancer
  • Cell biology
  • Immunology

ASJC Scopus subject areas

  • General


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