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.
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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.
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