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

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

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Article number	103538
Journal	iScience
Volume	24
Issue number	12
DOIs	https://doi.org/10.1016/j.isci.2021.103538
State	Published - Dec 17 2021

Funding

We thank Plateforme de Génomique, Institut Cochin Inserm U1016-CNRS UMR8104-Université de Paris for its technical assistance with the transcriptomic analysis. We thank Dr Le Gallo Matthieu (Inserm U1242, CLCC Eugène Marquis, Rennes) for his technical assistance in the purification of RNAs for transcriptomic analyses. This work was supported by INCa PLBIO ( PLBIO 2018-132 ), Ligue Contre le Cancer , Fondation ARC , Fondation de France (Price Jean Valade), ANR PRCE ( ANR-17-CE15-0027 ), and NIH grant R35CA197450 to M.E.P. We thank Plateforme de G?nomique, Institut Cochin Inserm U1016-CNRS UMR8104-Universit? de Paris for its technical assistance with the transcriptomic analysis. We thank Dr Le Gallo Matthieu (Inserm U1242, CLCC Eug?ne Marquis, Rennes) for his technical assistance in the purification of RNAs for transcriptomic analyses. This work was supported by INCa PLBIO (PLBIO 2018-132), Ligue Contre le Cancer, Fondation ARC, Fondation de France (Price Jean Valade), ANR PRCE (ANR-17-CE15-0027), and NIH grant R35CA197450 to M.E.P. J-P.G. and P.L. planned the experiments, conducted experiments, or analyzed data. C.G. and E.C-J. conducted experiments or analyzed data. M.P. and P.L. supervised the research, analyzed data, and wrote the manuscript. PL is involved in patents protecting the use of CD95 or CD95L in chronic inflammatory disorders and cancers (WO2014118317; WO2015189236; WO2015158810; WO2015104284; WO2017149012; WO2018130679).

Keywords

Cancer
Cell biology
Immunology

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2021.103538

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

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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AU - Peter, Marcus E.

AU - Legembre, Patrick

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N2 - 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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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