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

Pengfei Hou; Magdalena Zielonka; Lutgarde Serneels; Anna Martinez-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

doi:10.1016/j.molcel.2023.10.029

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

Mol Cell. 2023 Nov 16;83(22):4106-4122.e10. doi: 10.1016/j.molcel.2023.10.029. Epub 2023 Nov 16.

Affiliations

¹ Laboratory for the Research of Neurodegenerative Diseases, VIB Center for Brain & Disease Research, VIB, Leuven 3000, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium.
² Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium; Single Cell & Microfluidics Expertise Unit, VIB Center for Brain & Disease Research, VIB, Leuven 3000, Belgium.
³ Department of Neurosciences, Research Group Experimental Neurosurgery and Neuroanatomy, KU Leuven, Leuven 3000, Belgium.
⁴ Laboratory for the Research of Neurodegenerative Diseases, VIB Center for Brain & Disease Research, VIB, Leuven 3000, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium; Center for Human Genetics, KU Leuven, Leuven 3000, Belgium; Dementia Research Institute, Institute of Neurology, University College London, London WC1E 6BT, UK.
⁵ Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, Antwerp 2610, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp 2610, Belgium.
⁶ Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 4HN, UK.
⁷ Laboratory for the Research of Neurodegenerative Diseases, VIB Center for Brain & Disease Research, VIB, Leuven 3000, Belgium; Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium; Center for Human Genetics, KU Leuven, Leuven 3000, Belgium; Dementia Research Institute, Institute of Neurology, University College London, London WC1E 6BT, UK. Electronic address: [email protected].

PMID: 37977120
DOI: 10.1016/j.molcel.2023.10.029

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.

Keywords: Alzheimer's disease; intramembrane proteolysis; microglia; presenilin; substrate identification; tonic signaling; γ-secretase.

MeSH terms

Alzheimer Disease* / genetics
Amyloid Precursor Protein Secretases* / genetics
Amyloid Precursor Protein Secretases* / metabolism
Animals
Humans
Membrane Proteins / metabolism
Mice
Proteome / genetics
Signal Transduction

Substances

Amyloid Precursor Protein Secretases
Proteome
Membrane Proteins