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

doi:10.1016/j.isci.2021.103538

Abstract

SummaryCD95 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.

Highlights

Among women, breast cancer (BC) is the most common cause of cancer and the second leading cause of cancer death (DeSantis et al, 2016)
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 natural killer (NK) cells impairing tumor growth
Of CD95L, CD95/Kip1 ubiquitination-promoting complex protein 2 (KPC2) interaction contributes to the partial degradation of p105 (NF-kB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-kB-driven gene expression

Summary

Introduction

Breast cancer (BC) is the most common cause of cancer and the second leading cause of cancer death (DeSantis et al, 2016). The molecular classification of BC distinguishes luminal A and B expressing estrogen (ER) and/or progesterone receptors (PR), basal/triple negative breast cancer (TNBC), and human epidermal growth factor receptor 2 (HER2)-like tumors. This molecular taxonomy is clinically relevant, with basal/TNBC patients presenting the poorest clinical outcome with no targeted therapies available when compared with other molecular subtypes. Despite being resistant to CD95 mediated apoptosis, TNBCs maintain a very high amount of surface CD95 when compared with other breast cancers (Blok et al, 2017), and we recently found that CD95 loss in TNBC cells reprograms the immune landscape, by triggering a pro-inflammatory response unleashing the anti-tumor activity of natural killer (NK) cells (Qadir et al, 2021). The CD95dependent molecular mechanism responsible for the recruitment and activation of NK cells in TNBC remains to be elucidated

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