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The γ-secretase substrate proteome and its role in cell signaling regulation

Hou, P; Zielonka, M; Serneels, L; Martinez-Muriana, A; Fattorelli, N; Wolfs, L; Poovathingal, S; ... De Strooper, B; + view all (2023) The γ-secretase substrate proteome and its role in cell signaling regulation. Molecular Cell , 83 (22) 4106-4122.e10. 10.1016/j.molcel.2023.10.029. Green open access

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Abstract

γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.

Type: Article
Title: The γ-secretase substrate proteome and its role in cell signaling regulation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.molcel.2023.10.029
Publisher version: https://doi.org/10.1016/j.molcel.2023.10.029
Language: English
Additional information: © 2023 Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: γ-secretase, intramembrane proteolysis, substrate identification, microglia, tonic signaling, Alzheimer's disease, presenilin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10182418
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