The γ-secretase substrate proteome and its role in cell signaling regulation
Pengfei Hou, Magdalena Zielonka, Lutgarde Serneels, Anna Martínez‐Muriana, Nicola Fattorelli, Leen Wolfs, Suresh Poovathingal, Dries T’Syen, Sriram Balusu, Tom Theys, Mark Fiers, Renzo Mancuso, Andrew J.M. Howden, Bart De Strooper
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.