title: γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling.
abstract: 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.
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Chhibber-Goel
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Coleman-Vaughan
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: Vishal
authors.initials: V
authors.lastname: Agrawal
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: Neha
authors.initials: N
authors.lastname: Sawhney
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: Emer
authors.initials: E
authors.lastname: Hickey
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland.
authors.forename: James C
authors.initials: JC
authors.lastname: Powell
authors.affiliation: From the Signal Transduction Laboratory, School of Biochemistry and Cell Biology, ABCRF, 3.41 Western Gateway Building, Western Road, University College Cork, Cork T12 YN60, Ireland. Electronic address: jv.mccarthy@ucc.ie.
authors.forename: Justin V
authors.initials: JV
authors.lastname: McCarthy
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D054360:Chemokine CXCL1; D053763:Presenilins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases
keywords: NF-kappaB; apoptosis; c-Jun N-terminal kinase (JNK); cell death; gamma-secretase; presenilin; receptor internalization; tumor necrosis factor (TNF)