The ␥-secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptormediated 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 membranebound 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.The biological activities of the tumor necrosis factor-␣ (TNF) pro-inflammatory cytokine are resolved by two distinct cell surface receptors, TNFR1 3 and TNFR2, which elicit a diversity of cellular responses, such as inflammation, cell proliferation, cell differentiation, and initiation of apoptosis (1-10). TNFR1 initiates either pro-inflammatory or pro-apoptotic signaling through the selective recruitment of intracellular adaptor and effector proteins (1,3,6,7,11). Ligand binding and trimerization of TNFR1 enables the recruitment of TNFR1-associated death domain protein (TRADD) (12, 13), which functions as a scaffold enabling the recruitment of receptorinteracting protein kinase 1 (RIPK1) (14 -16), TNF receptorassociated factor 2 (TRAF2) or TRAF5 (12), and the cellular inhibitor of apoptosis proteins (cIAPs) cIAP1 and cIAP2 (11), which collectively form a signaling composite called complex I (17-19). The resulting lysine 63-linked polyubiquitination of RIPK1 by TRAF2 and the cIAPs (20 -24) enables an interaction with the IB kinase complex that mediates the phosphorylation and degradation of IB-inhibitory proteins and activation of the transcription factor NF-B to promote non-apoptotic signaling pathways (25-27). NF-B also increases expression of anti-apoptotic genes, including cIAPs and FLICE inhibitory protein (c-FLIP), further ensuring a non-apoptotic signaling pathway.The importance of receptor internalization as a regulatory mechanism for the segregation and divergence of intracellular signaling pathways is highlighted by studies on internalization of TNFR1 and TNFR2, the Fas receptor (FasR/CD95), IL-1 receptor I, Toll-like receptor 4, and TRAIL receptors (18, 28 -33). The current favored m...
Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.
SARS-CoV-2 cell–cell fusion and syncytiation is an emerging pathomechanism in COVID-19, but the precise factors contributing to the process remain ill-defined. In this study, we show that metalloproteases promote SARS-CoV-2 spike protein-induced syncytiation in the absence of established serine proteases using in vitro cell–cell fusion assays. We also show that metalloproteases promote S2′-activation of the SARS-CoV-2 spike protein, and that metalloprotease inhibition significantly reduces the syncytiation of SARS-CoV-2 variants of concern. In the presence of serine proteases, however, metalloprotease inhibition does not reduce spike protein-induced syncytiation and a combination of metalloprotease and serine protease inhibition is necessitated. Moreover, we show that the spike protein induces metalloprotease-dependent ectodomain shedding of the ACE2 receptor and that ACE2 shedding contributes to spike protein-induced syncytiation. These observations suggest a benefit to the incorporation of pharmacological inhibitors of metalloproteases into treatment strategies for patients with COVID-19.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.