γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling*
| Autor: | Neha Sawhney, James C. Powell, Vishal Agrawal, Jyoti Chhibber-Goel, Emer Hickey, Justin V. McCarthy, Caroline Coleman-Vaughan |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAP Kinase Kinase 4 medicine.medical_treatment Chemokine CXCL1 Apoptosis Biochemistry Regulated Intramembrane Proteolysis Presenilin Cell Line 03 medical and health sciences medicine Animals Humans Receptor Molecular Biology Gamma secretase Mice Knockout biology Chemistry Tumor Necrosis Factor-alpha Presenilins Cell Biology respiratory system Cell biology Enzyme Activation Mice Inbred C57BL 030104 developmental biology Cytokine Ectodomain Receptors Tumor Necrosis Factor Type I Proteolysis biology.protein Signal transduction Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Gene Deletion Signal Transduction |
| Popis: | The γ-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 γ-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 γ-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 γ-secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and γ-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 γ-secretase substrate and suggest that γ-secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the γ-secretase protease to pro-inflammatory cytokine signaling. |
| Databáze: | OpenAIRE |
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