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Title
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The y-secretase substrate proteome and its role in cell signaling regulation
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Author
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Abstract
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| y-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased y-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 y-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 y-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 y-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell. |
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Language
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English
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Source (journal)
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Molecular cell. - Cambridge, Mass.
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Publication
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Cambridge
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Cell press
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2023
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ISSN
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1097-2765
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DOI
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10.1016/J.MOLCEL.2023.10.029
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Volume/pages
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83
:22
(2023)
, p. 4106-4122.e10
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ISI
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001149590100001
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Pubmed ID
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37977120
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Full text (Publisher's DOI)
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Full text (open access)
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