Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.
Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-kappaB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-kappaB activity through RIP1 cleavage.
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Cédric
C
Institut National de la Santé et de la Recherche Médicale (INSERM) U517, Dijon, France.
Cathelin
Séverine
S
Launay
Sophie
S
Filomenko
Rodolphe
R
Prévotat
Laurent
L
L'Ollivier
Coralie
C
Gyan
Emmanuel
E
Micheau
Olivier
O
Grant
Steven
S
Dubart-Kupperschmitt
Anne
A
Fontenay
Michaëla
M
Solary
Eric
E
D053181:Caspase 8 / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
C119724:AGFG1 protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D016173:Macrophage Colony-Stimulating Factor; D053181:Caspase 8