Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 11, Pages 5971-5985Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.679076
Keywords
apoptosis; c-Jun N-terminal kinase (JNK); cell death; gamma-secretase; NF-kappaB; presenilin; receptor internalization; tumor necrosis factor (TNF)
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Funding
- Science Foundation Ireland [02/IN1/B218, 09/IN.1/B2624]
- Irish Research Council for Science, Engineering, and Technology [RS/2012/407]
- Science Foundation Ireland (SFI) [09/IN.1/B2624] Funding Source: Science Foundation Ireland (SFI)
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The -secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptor-mediated intracellular signaling events, which have a central role in Alzheimer disease, cancer progression, and immune surveillance. An increasing number of -secretase substrates have a role in cytokine signaling, including the IL-6 receptor, IL-1 receptor type I, and IL-1 receptor type II. In this study, we show that following TNF-converting enzyme-mediated ectodomain shedding of TNF type I receptor (TNFR1), the membrane-bound TNFR1 C-terminal fragment is subsequently cleaved by -secretase to generate a cytosolic TNFR1 intracellular domain. We also show that clathrin-mediated internalization of TNFR1 C-terminal fragment is a prerequisite for efficient -secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and -secretase activity, TNF-mediated JNK activation was prevented, assembly of the TNFR1 pro-apoptotic complex II was reduced, and TNF-induced apoptosis was inhibited. These observations demonstrate that TNFR1 is a -secretase substrate and suggest that -secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the -secretase protease to pro-inflammatory cytokine signaling.
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